CN113621071A - 一种t细胞抗原受体、其多聚体复合物及其制备方法和应用 - Google Patents
一种t细胞抗原受体、其多聚体复合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提供了一种T细胞抗原受体、表达T细胞抗原受体(TCR)的免疫细胞,及其制备方法和应用。本发明所述的TCR能够特异性地识别对应的pMHC复合物,激活TCR‑T细胞,进而产生高水平的细胞因子IFNγ、IL2、TNFα,显著地杀伤靶细胞并延长负荷肿瘤的小鼠的寿命。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种抗体或其抗原结合片段、T细胞抗原受体、多聚体复合物,及其制备方法和应用。
背景技术
EB病毒(Epstein-Barr virus,EBV)是Epstein和Barr于1964年从伯基特氏淋巴瘤(Burkitt’s lymphoma,BL)的样本中分离的一种γ疱疹病毒,也是第一个被公认的致瘤病毒。EBV原发感染主要发生在人类口咽部的上皮细胞,后因其显著的嗜B淋巴细胞特性,能感染B细胞并在记忆B细胞中长期潜伏存在,导致被感染者终身携带,故而在成人血清中病毒抗体的阳性率超过90%。尽管EBV感染对绝大多数免疫功能正常的人并不会构成太大的威胁,但对于患有先天性或获得性免疫缺陷的人群,EBV会导致多种危及生命的疾病。此外,EBV潜伏感染表达的蛋白(6个核蛋白EBNA1、2、3A、3B和3C,EBNA-LP以及3个潜伏期膜蛋白LMP1、LMP2A、LMP2B)能刺激细胞增生和转化,已被证实与多种恶性肿瘤的发生、发展、临床预后直接相关,包括EBV相关的移植后淋巴细胞增生性疾病(EBV related post-transplant lymphoproliferative diseases,EBV-PTLD)、伯基特氏淋巴瘤、霍奇金淋巴瘤(Hodgkin’s lymphoma,HL)、鼻咽癌(Nasopharyngeal carcinoma,NPC)、胃癌(Gastriccancer)等。根据潜伏蛋白在这些疾病中的差异表达,将EBV潜伏型分为I、II、III期。目前,靶向EB病毒的抗病毒治疗由于耐药性以及严重副作用等问题,尚不能实现对多种EBV相关疾病的有效控制。
Papadopounds等最先发现,输注EBV健康携带者的淋巴细胞可以治愈PTLD患者,随后临床发展出自体EBV-CTLs细胞疗法。目前EBV-CTLs已在EBV相关淋巴瘤和鼻咽癌中开展了临床应用,发现其人体内安全性良好并有一定的治疗效果,但体外培养的CTLs的诸多不足也限制了其临床疗效。首先,CTLs中肿瘤相关EBV抗原的特异性T细胞数量较少(<0.05%),因此一般需进行大剂量(大于1010)的多次回输(4-6次);其次,较长的制备周期导致等待治疗时间长,伴随着的T细胞分化亚群的变化进一步导致其体内功能弱;此外,制备的细胞因人而异,疗效难以保证。因此,亟待开发更特异性、体内杀伤肿瘤能力更强、更持久的靶向EBV抗原的细胞免疫疗法,用于EBV相关鼻咽癌或淋巴瘤的治疗。
T细胞是获得性免疫系统的重要组成部分,介导了病原体、自身病变细胞和肿瘤的清除,是维持机体稳态的防护力量。T细胞受体(T cell receptor,TCR)是T细胞的身份标识,TCR通过对靶细胞主要组织相容性复合体(MHC)及所提呈的抗原复合体的识别,引发T细胞的激活和一系列后续细胞信号传递和其他生理反应,从而使得抗原特异性的T细胞对其靶细胞发挥免疫效应。TCR-T细胞疗法是将肿瘤/病毒抗原肽高特异性、高亲和力的T细胞受体克隆后,通过基因转导技术导入患者自体的T细胞,使自体T细胞可以特异的识别肿瘤/病毒的抗原多肽,进而清除肿瘤或病原体的技术。与CAR-T相比,TCR-T疗法可识别更广泛的肿瘤抗原(胞内蛋白和膜蛋白),呈现更加强的杀伤作用的同时伴随较低细胞因子风暴,对实体瘤的治疗有更大的潜力。目前TCR-T疗法已在肺癌、结肠癌、滑膜细胞肉瘤等多种实体肿瘤的临床试验中观察到显著疗效,但因为主要针对的靶点多为肿瘤相关抗原如CEA、gp100、MART-1、MAGA-A3和NY-ESO-1等,发现了脱靶效应和毒副作用。对于EBV感染相关的恶性疾病,EBV抗原作为外来抗原,有较强的免疫原性并且不易发生脱靶效应,是理想的潜在靶标。
EBV潜伏膜蛋白LMP2A能促进细胞的增殖、存活和迁移并协助上皮间质转化,是所有II型和III型疾病/恶性肿瘤中表达的EBV主要基因之一。据文献报道,在回输的EBV-CTL中,LMP2特异性的CTL细胞比例与其临床疗效密切相关,这些证据表明LMP2可以作为EBV感染相关的II/III型疾病如鼻咽癌治疗的靶点。例如:专利CN1526072A公开了EBV肿瘤相关潜伏膜蛋白的胞外结构域的鉴定方法和与之反应的抗体试剂的选择方法,并具体公开了EBVLMP2胞外域的氨基酸序列。专利CN1269804A中公开的众多EBV的T细胞CTL表位。专利CN108289950A公开了一种特异于人HLA呈递的EBV LMP2的T细胞受体样抗体药剂,其中所述的T细胞受体识别的抗原肽表位为CLGGLLTMV。专利WO2017085471公开了一种特异识别抗原肽为SSCSSCPLSK的TCR序列。此外,非专利文献Dual non-contiguous peptide occupancyof HLA class I evoke antiviral human CD8 T cell response and form neo-epitopes with self-antigens(Ziwei Xiao等,Sci Rep,2017)公开了在HLA-A*1101个体中,有7/8的个体利用相同的TRBV4-1片段作为SSC的主要识别特异性。专利CN109306005A公开了一种EB病毒特异性T细胞抗原受体及其应用。但是,现有技术中均未公开本发明所述的TCR。
发明内容
本发明发现LMP2蛋白的HLA-A*1101限制肽SSCSSCPLSK/SSCSSCPLTK是免疫原性较强的抗原表位,可以引发机体产生特异的T淋巴细胞和相应的免疫反应,因此,本发明提供了多种可以特异性结合EBV潜伏期蛋白LMP2肽(包含序列SSCSSCPLSK/SSCSSCPLTK)的T细胞抗原受体及其在制备治疗与EBV相关疾病的药物组合物中的应用。本发明所述的TCR能够特异性地识别对应的pMHC复合物,激活TCR-T细胞,进而产生高水平的细胞因子IFNγ、IL2、TNFα,显著地杀伤靶细胞并延长负荷肿瘤的小鼠的寿命。
具体的,本发明的第一方面,提供了一种T细胞抗原受体,所述的T细胞抗原受体特异性结合EBV潜伏期膜蛋白LMP2,其中,结合表位包含SEQ ID NO:5和/或6。
优选的,所述的EBV潜伏期膜蛋白LMP2包含SEQ ID NO:37和/或SEQ ID NO:38所示的氨基酸序列,或者包含与SEQ ID NO:37和/或SEQ ID NO:38具有至少80%同源性的氨基酸序列。
优选的,所述的T细胞抗原受体通过主要组织相容性复合物分子(MHC)的呈递,与来自EBV潜伏期膜蛋白LMP2肽特异性结合。
优选的,所述的T细胞抗原受体至少包含一个α链可变区和/或β链可变区。
优选的,所述的T细胞抗原受体是αβ异二聚体。
优选的,所述的T细胞抗原受体包含α链的CDR1α-CDR3α和β链的CDR1β-CDR3β。
CDR1α的氨基酸序列如SEQ ID NO:212所示或与SEQ ID NO:212所示氨基酸序列具有至少80%同源性,CDR2α的氨基酸序列如SEQ ID NO:213所示或与SEQ ID NO:213所示氨基酸序列具有至少80%同源性,CDR3α的氨基酸序列如SEQ ID NO:214-215中的任一种或与SEQ ID NO:214-215中任一种所示氨基酸序列具有至少80%同源性,CDR1β的氨基酸序列如SEQ ID NO:217或与SEQ ID NO:217所示氨基酸序列具有至少80%同源性,CDR2β的氨基酸序列如SEQ ID NO:219或与SEQ ID NO:219所示氨基酸序列具有至少80%同源性,CDR3β的氨基酸序列如SEQ ID NO:221、251中的任一种或与SEQ ID NO:221、251中任一种所示氨基酸序列具有至少80%同源性。
所述的CDR1α-CDR3α及CDR1β-CDR3β选自下列任一组:
CDR1α的氨基酸序列如SEQ ID NO:212所示或与SEQ ID NO:212所示氨基酸序列具有至少80%同源性,CDR2α的氨基酸序列如SEQ ID NO:213所示或与SEQ ID NO:213所示氨基酸序列具有至少80%同源性,CDR3α的氨基酸序列如SEQ ID NO:214-216中的任一种或与SEQ ID NO:214-216中任一种所示氨基酸序列具有至少80%同源性,CDR1β的氨基酸序列如SEQ ID NO:217-218中任一种或与SEQ ID NO:217-218中任一种所示氨基酸序列具有至少80%同源性,CDR2β的氨基酸序列如SEQ ID NO:219-220中任一种或与SEQ ID NO:219-220中任一种所示氨基酸序列具有至少80%同源性,CDR3β的氨基酸序列如SEQ ID NO:221-224中的任一种或与SEQ ID NO:221-224中任一种所示氨基酸序列具有至少80%同源性。
所述的CDR1α-CDR3α及CDR1β-CDR3β选自下列任一组:
优选的,所述的α链的氨基酸序列如SEQ ID NO:31-36所示,或与SEQ ID NO:31-36所示氨基酸序列具有至少80%同源性。
优选的,所述的β链的氨基酸序列如SEQ ID NO:25-30所示,或与SEQ ID NO:25-30所示氨基酸序列具有至少80%同源性。
优选的,所述的T细胞抗原受体的氨基酸序列选自SEQ ID NO:19-24中的任一种或与SEQ ID NO:19-24任一种所示氨基酸序列具有至少80%同源性。
优选的,所述T细胞抗原受体的α链和β链通过linker序列连接,linker序列优选为furin-SGSG-p2A序列(以下简写fp2A)。
优选的,所述的连接顺序可以为α链、fp2A、β链,或者β链、fp2A、α链。
在本发明的一个具体实施方式中,所述的连接顺序为β链、fp2A、α链。
优选的,所述的T细胞抗原受体通过MHC或多聚体复合物的呈递,与EBV潜伏期膜蛋白LMP2特异性结合。其中,所述的多聚体复合物包含抗原肽,所述的抗原肽包含SEQ ID NO:5和/或6。优选的,所述的多聚体复合物还包括单体,生物素分子,以及链霉亲和素分子或亲和素分子,其中,所述单体包括MHC分子α链胞外区和β2m链,所述单体与所述生物素分子偶联,所述生物素分子与所述链霉亲和素或亲和素分子结合。
本发明的第二方面,提供了一种抗体或其抗原结合片段,所述的抗体或其抗原结合片段特异性结合EBV潜伏期膜蛋白LMP2,其中,所述LMP2的结合表位包含SEQ ID NO:5和/或6。
优选的,所述抗体或其抗原结合片段包含α链的CDR1α-CDR3α和β链的CDR1β-CDR3β,其中,CDR1α的氨基酸序列如SEQ ID NO:212所示或与SEQ ID NO:212所示氨基酸序列具有至少80%同源性,CDR2α的氨基酸序列如SEQ ID NO:213所示或与SEQ ID NO:213所示氨基酸序列具有至少80%同源性,CDR3α的氨基酸序列如SEQ ID NO:214-216中的任一种或与SEQ ID NO:214-216中任一种所示氨基酸序列具有至少80%同源性,CDR1β的氨基酸序列如SEQ ID NO:217-218中的任一种或与SEQ ID NO:217-218中任一种所示氨基酸序列具有至少80%同源性,CDR2β的氨基酸序列如SEQ ID NO:219-220中的任一种或与SEQ ID NO:219-220中任一种所示氨基酸序列具有至少80%同源性,CDR3β的氨基酸序列如SEQ ID NO:221-224、251中的任一种或与SEQ ID NO:221-224、251中任一种所示氨基酸序列具有至少80%同源性。
在本发明的一个具体实施方式中,所述的CDR1α-CDR3α及CDR1β-CDR3β选自下列任一组:
在本发明的一个具体实施方式中,所述的抗体或其抗原结合片段的氨基酸序列选自SEQ ID NO:19-24中的任一种或与SEQ ID NO:19-24任一种所示氨基酸序列具有至少80%同源性。
优选的,所述的抗体或其抗原结合片段还可以包含如Fab、Fab’、Fab’-SH、Fv、scFv、(Fab’)2、单结构域抗体、双抗体(dAb)或线性抗体的片段。
本发明的第三方面,提供了一种核酸,所述的核酸编码上述的抗体或其抗原结合片段,或者上述的T细胞抗原受体。
在本发明的一个具体实施方式中,所述的编码抗体或其抗原结合片段,或者T细胞抗原受体的核苷酸序列选自SEQ ID NO:39-44中的任一种或与SEQ ID NO:39-44任一种所示核苷酸序列具有至少80%同源性。
优选的,所述的核苷酸序列可以是经密码子优化的。进一步优选的,所述的密码子优化包括将病毒等使用的大量稀有密码子变为对应的哺乳动物密码子和/或移除mRNA不稳定基序和/或隐藏的剪接位点。
本发明的第四方面,提供了一种表达载体,所述的表达载体包含上述的核酸。
优选的,所述的表达载体能够在体内或体外或离体条件下表达。进一步优选的,所述的表达载体在体内细胞中持续高水平表达。
优选的,所述的表达载体为原核表达载体或慢病毒表达载体。
进一步优选的,所述的原核表达载体为大肠杆菌系列。在本发明的一个具体实施方式中,所述的表达载体为pET-26b或pET28a+。
在本发明的一个具体实施方式中,所述的表达载体为pHAGE-IRES-RFP。
进一步优选的,所述的表达载体中β链、α链与骨架载体的连接顺序为启动子、β链、furin-p2A、α链、IRES和RFP序列。
本发明的第五方面,提供了一种宿主细胞,所述的宿主细胞包含上述的核酸或上述的表达载体。
优选的,所述的宿主细胞可以是真核的或原核的。更优选的,所述的宿主细胞为酵母细胞、293细胞、CHO细胞、大肠杆菌等。
在本发明的一个具体实施方式中,所述的宿主细胞为Stbl3、BL21或transetta。
本发明的第六方面,提供了一种免疫细胞,所述的免疫细胞表达上述的抗体或其抗原结合片段,或者上述的T细胞抗原受体。
优选的,所述的免疫细胞包括但不限于淋巴细胞(包括T细胞、B细胞)。进一步,所述免疫细胞是B细胞,所述B细胞表达上述的抗体或其抗原结合片段。所述免疫细胞是T细胞,所述T细胞的T细胞抗原受体结构如上所限定。
本发明的第七方面,提供了一种免疫细胞的制备方法,包括将编码上述抗体或其抗原结合片段,或者所述的T细胞抗原受体的核酸序列转染至免疫细胞中表达获得。
优选的,所述的免疫细胞包括但不限于淋巴细胞(包括T细胞、B细胞)。进一步,所述免疫细胞是B细胞,所述B细胞表达上述的抗体或其抗原结合片段。所述免疫细胞是T细胞,所述T细胞的T细胞抗原受体结构如上所限定。
优选的,还包括敲除细胞内源性TCR的步骤。具体的,可以为将靶向内源TCR的guide构建至慢病毒载体,与包装质粒、转染试剂共转至T细胞。
本发明的第八方面,提供了一种重组T细胞的制备方法,包括如下步骤:
1)从阳性T细胞克隆得到编码上述的T细胞抗原受体的核酸序列;
2)分离、培养原代T细胞;
3)将步骤1)得到的核酸序列递送至步骤2)所述的原代T细胞中,获得表达上述T细胞抗原受体的重组T细胞。
优选的,所述的T细胞选自造血干细胞或外周血淋巴细胞(PBL)源T细胞。
本发明的第九方面,提供了一种抗体或其抗原结合片段或T细胞抗原受体的制备方法,包括如下步骤:
(1)从阳性T细胞克隆得到编码上述抗体或其抗原结合片段,或上述的T细胞抗原受体的核酸序列;
(2)将步骤(1)得到的核酸序列连接至载体骨架,获得表达载体;
(3)将步骤(2)获得的表达载体转化至宿主细胞,然后诱导其表达;
(4)获得抗体或其抗原结合片段或者T细胞抗原受体。
优选的,所述的阳性T细胞为与MHC呈递的EBV潜伏期膜蛋白LMP2肽特异性结合。进一步优选的,所述的MHC呈递的EBV潜伏期膜蛋白LMP2肽为单体或多聚体复合物。
本发明的第十方面,提供了一种多聚体复合物,其包含上述任一所述的T细胞抗原受体。
优选的,其还包括单体,生物素分子,以及带荧光标记的链霉亲和素分子或亲和素分子,其中,所述单体包括抗原肽、MHC分子α链胞外区和β2m链,所述单体与所述生物素分子偶联,所述生物素分子与所述链霉亲和素或亲和素分子结合。
优选的,所述的MHC分子α链胞外区的C端连接avi-tag序列。
优选的,所述的MHC分子α链胞外区不含信号肽序列。并在成熟肽序列前面添加M氨基酸。
优选的,所述的β2m链不含有信号肽序列。且在成熟肽序列前面添加M和A两个氨基酸。
在本发明的一个具体实施方式中,所述的β2m链为不含信号肽且在成熟肽序列前加了两个氨基酸,优选为M、A。
优选的,所述的抗原肽包含SEQ ID NO:5和/或6。
在本发明的一个具体实施方式中,所述的多聚体复合物包含:
(1)T细胞抗原受体;优选为SEQ ID NO:19-24中的任一种或与SEQ ID NO:19-24任一种所示氨基酸序列具有至少80%同源性。
(3)单体,所述的单体包括抗原肽、C端连接avi-tag序列的MHC分子α链胞外区和不含信号肽的β2m链;所述的抗原肽选自SEQ ID NO:5和/或6;
(4)生物素分子;以及
(5)链霉亲和素分子或亲和素分子;其中,所述单体与所述生物素分子偶联,所述生物素分子与所述链霉亲和素或亲和素结合。
优选的,所述的MHC分子为MHC I类分子或MHC II类分子。更优选的,所述的MHC分子为MHC I类分子。
优选的,所述的MHC分子为HLA-A*1101。
在本发明的一个具体实施方式中,所述的MHC分子α链的氨基酸序列如SEQ ID NO:1所示或SEQ ID NO:1所示氨基酸序列具有至少80%同源性。
在本发明的一个具体实施方式中,所述的MHC分子的β2m链如SEQ ID NO:3所示或SEQ ID NO:3所示氨基酸序列具有至少80%同源性。
为提高抗原肽-MHC四聚体与T细胞抗原受体结合的特异性,所述的单体还包括至少一个氨基酸的化学修饰、突变、插入和/或缺失。
优选的,所述的MHC分子α链胞外区和β2m链为非共价结合。
优选的,所述的多聚体复合物至少包含一个单体。
优选的,每个单体至少偶联一个生物素分子。
本发明的第十一方面,提供了一种上述的多聚体复合物的制备方法,包括如下步骤:
I)表达和纯化在C端连接avi-tag序列的MHC分子α链胞外区和β2m链;
II)将抗原肽、步骤I)获得的在C端连接avi-tag序列的MHC分子α链胞外区和β2m链复性折叠,制备单体;
III)将步骤II)制备的单体生物素化,获得生物素化的单体;
IV)将步骤III)获得的生物素化的单体与带荧光标记的链霉亲和素或亲和素反应,制备抗原肽-MHC四聚体;
V)将步骤IV)得到的抗原肽-MHC分子四聚体与T细胞共孵育,形成T细胞抗原受体与抗原肽-MHC分子四聚体复合物,钓取特异性T细胞抗原受体。
优选的,所述步骤I)中包括分别克隆在编码C端连接avi-tag序列的MHC分子α链胞外区的核苷酸序列和MHC分子β2m链的核苷酸序列,连接至载体后,转化到表达菌中培养,加入诱导剂,提取包涵体。
进一步优选的,所述表达菌培养至OD600值在0.2-0.4之间。
进一步优选的,所述诱导剂加入后的最终摩尔浓度为0.5-1mM。
优选的,诱导表达4-6h。
优选的,所述步骤II)包括β2m链的复性折叠,即将抗原肽、MHC分子β2m链、C端连接avi-tag序列的MHC分子α链胞外区依次加入稀释缓冲液中避光水浴,其中,所述的β2m链的复性折叠包括包涵体变性、加入蛋白酶抑制剂,而后透析。
优选的,所述的抗原肽、不含信号肽的β2m链与C端连接avi-tag序列的α链的摩尔比为(30-50):(2-2.5):1。进一步优选为40:2:1。
优选的,所述步骤II)中还包含纯化单体的步骤。
优选的,所述步骤III)中的生物素化是在BirA酶的催化下,将单体与BiomixA、BiomixB结合。
优选的,所述步骤III)中还包括纯化生物素化单体的步骤。
优选的,所述步骤IV)中的单体与链霉亲和素反应的摩尔比为(4-7):1。
本发明的第十二方面,提供了一种上述多聚体复合物在制备、筛选或检测本发明所述抗体或其抗原结合片段或T细胞抗原受体中的应用。
本发明的第十三方面,提供了上述的抗体或其抗原结合片段、上述的T细胞抗原受体、上述的核酸、上述的表达载体、上述的宿主细胞、上述的免疫细胞或者上述的多聚体复合物在制备诊断或治疗与EBV相关疾病的产品中的应用。
优选的,所述的与EBV相关疾病选自传染性单核细胞增多症、连锁淋巴细胞增生综合症、病毒性嗜血细胞综合症、口腔毛状黏膜白斑病、病毒性脑膜炎、周围神经炎、病毒性肺炎、病毒性心肌炎、鼻咽癌、霍奇金淋巴瘤、伯基特淋巴瘤、胃癌、肝细胞癌、淋巴上皮样肉瘤、唾液腺肿瘤、乳腺癌、胸腺瘤、原发性渗出性淋巴瘤或B/T/NK细胞淋巴瘤。
本发明的第十四方面,提供了上述的抗体或其抗原结合片段、上述的T细胞抗原受体、上述的核酸、上述的表达载体、上述的宿主细胞、上述的免疫细胞或者上述的多聚体复合物在T细胞标记、检测、细胞分选或活化中的应用。
本发明的第十五方面,提供了一种药物组合物,所述的药物组合物包含下列任一组:
i)本发明所述的抗体或其抗原结合片段;
ii)本发明所述的T细胞抗原受体;
iii)本发明所述的核酸;
iv)本发明所述的表达载体;
v)本发明所述的宿主细胞;
vi)本发明所述的免疫细胞;或
vii)本发明所述的多聚体复合物。
优选的,所述的药物组合物还可以包含药学上可接受的辅料。
优选的,所述的药物组合物还可以与其他治疗剂共同使用。进一步优选的,所述的治疗剂可以为免疫调节剂。
本发明的第十六方面,提供了一种试剂盒,所述的试剂盒包含下列任一组:
i)本发明所述的抗体或其抗原结合片段;
ii)本发明所述的T细胞抗原受体;
iii)本发明所述的核酸;
iv)本发明所述的表达载体;
v)本发明所述的宿主细胞;
vi)本发明所述的免疫细胞;或
vii)本发明所述的多聚体复合物。
本发明的第十七方面,涉及一种检测EBV LMP2的方法,所述的方法包括将待检测样品与本发明所述的抗体或其抗原结合片段或者T细胞抗原受体接触,然后检测EBV LMP2与抗体或其抗原结合片段或者T细胞抗原受体形成的复合物。
优选的,所述检测EBV LMP2为检测EBV LMP2的存在或含量。其中,所述的存在表示有无,所述的含量可以为表达量或蛋白浓度等。
优选的,所述的抗体或其抗原结合片段或者T细胞抗原受体包括可检测的标记物。
在本发明的一个具体实施方式中,所述的标记物可以是His和/或HA。
本发明所述的检测EBV LMP2的方法,不是疾病的诊断方法。首先,待检测样品并非生物体或其离体组织或细胞,其次,即便生物体中存在EBV LMP2或者包含一定浓度或表达水平的EBV LMP2也并非确定是疾病,只是一种可能性。
本发明的第十八方面,涉及一种治疗与EBV相关疾病的方法,所述的方法包括给予个体有效量的本发明所述抗体或其抗原结合片段、所述的T细胞抗原受体、所述的核酸、所述的表达载体、所述的宿主细胞、所述的免疫细胞或所述的药物组合物。
优选的,所述的治疗与EBV相关疾病的方法包括将本发明所述的T细胞抗原受体定位在与EBV相关疾病(优选为肿瘤或转移性肿瘤)的附近,以提高毒素或免疫刺激剂的效力。
进一步,所述EBV相关疾病选自传染性单核细胞增多症、连锁淋巴细胞增生综合症、病毒性嗜血细胞综合症、口腔毛状黏膜白斑病、病毒性脑膜炎、周围神经炎、病毒性肺炎、病毒性心肌炎、鼻咽癌、霍奇金淋巴瘤、伯基特淋巴瘤、胃癌、肝细胞癌、淋巴上皮样肉瘤、唾液腺肿瘤、乳腺癌、胸腺瘤、原发性渗出性淋巴瘤或B/T/NK细胞淋巴瘤。
本发明的第十九方面,涉及一种诊断与EBV相关疾病的方法,所述的方法包括取样,将样品与本发明所述的抗体或其抗原结合片段或T细胞抗原受体接触,然后检测EBVLMP2与抗体或其抗原结合片段或T细胞抗原受体形成的复合物。优选的,所述的抗体或其抗原结合片段或T细胞抗原受体包括可检测的标记物。
本发明所述的TCR能够特异性地识别对应的EBV LMP2抗原肽或pMHC复合物,激活TCR-T细胞,进而产生高水平的细胞因子IFNγ、IL2、TNFα,显著地杀伤靶细胞并延长负荷肿瘤的小鼠的寿命。
本发明所述的“LMP2”包含LMP2A和LMP2B。LMP2A和LPM2B的区别在于LMP2A中存在一个额外的N-末端119个氨基酸的胞质结构域,除此之外LMP2A和LPM2B的结构均相同。同时,无论是LMP2A或LMP2B均包含本发明所述的T细胞抗原受体或者抗体结合的抗原肽区域。
本发明所述的“同源性”是指在使用氨基酸序列或核苷酸序列的方面,本领域技术人员可以在不改变原序列主要结构或功能的前提下,根据实际工作需要对序列进行调整,使使用序列与本发明所述的具体序列相比,具有(包括但不限于)1%,2%,3%,4%,5%,6%,7%,8%,9%,10%,11%,12%,13%,14%,15%,16%,17%,18%,19%,20%,21%,22%,23%,24%,25%,26%,27%,28%,29%,30%,31%,32%,33%,34%,35%,36%,37%,38%,39%,40%,41%,42%,43%,44%,45%,46%,47%,48%,49%,50%,51%,52%,53%,54%,55%,56%,57%,58%,59%,60%,70%,80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%的同源性。例如,本发明所述的“与SEQ ID NO:19-24中任一种所示氨基酸序列具有至少80%同源性”即为在保留与EBV潜伏期膜蛋白LMP2肽表位:MHC复合物结合功能的前提下,可以根据实际工作需要对SEQ ID NO:19、20、21、22、23或24进行调整,例如取代、缺失和/或插入一个或多个氨基酸等。其中,所述的至少80%包括但不限于80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,99%或100%。
本发明所述的“个体”包括但不限于人或非人哺乳动物。优选的,所述的非人哺乳动物包括但不限于小鼠、大鼠、猴子、猪或兔子等。
本发明所述的“有效量”是指在以单个或多个剂量给予至患者或器官之后提供所希望的治疗或预防的本发明所述的产品的量或剂量。
本发明所述的“诊断”是指以查明患者过去、诊断时或将来是否患有疾病或病症,或者是查明疾病的进展或将来可能的进展,或者是评估患者对治疗的反应。
本发明所述的“治疗”表示减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性,但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除,且是指在疾病已开始发展后改善疾病或病理状态的体征、症状等等的治疗干预。
本发明所述的“产品”包括但不限于本发明所述的抗体或其抗原结合片段、所述的T细胞抗原受体、所述的核酸、所述的表达载体、所述的宿主细胞、所述的免疫细胞或者所述的多聚体复合物,以及其他辅助或与上述上述产品协同的试剂。
本发明所述的“产品”可以为试剂盒、芯片、抗体偶联物或多功能抗体等药物组合物。
本发明所述的“和/或”包括择一列出的项目以及任何数量的项目组合。
本发明所述的“包括”是开放式的描述,含有所描述的指定成分或步骤,以及不会实质上影响技术效果的其他指定成分或步骤。
本发明所述的“TRBV”表示是T细胞受体β可变区,“TRBC”表示是T细胞受体β恒定区。
附图说明
以下,结合附图来详细说明本发明的实施例,其中:
图1:单体的SDS PAGE检测结果,其中,M为蛋白Marker,条带1、2为单体;
图2:A1101-SSCSSCPLSK-四聚体染色结果,具体为A1101-SSCSSCPLSK-四聚体在体积梯度检测实验中与商业化四聚体的对比;
图3:四聚体染色结果,具体为A1101-SSCSSCPLSK-四聚体及A1101-SSCSSCPLTK-四聚体染色结果。
图4:TCRβ链和α链在pHAGE载体中连接示意图,其中连接顺序依次为启动子、β链、furin-p2A、α链、IRES和RFP序列;
图5:流式细胞检测HLA-A*1101表位SSCSSCPLSK(LSK)和SSCSSCPLTK(LTK)特异性TCR与四聚体探针结合的亲和力;
图6:不同浓度的LSK肽段刺激下JC5-TCR细胞的IL-2产量;
图7:LSK表位特异性TCR的EC50统计结果,其中public TCR代表CDR3基序保守的TCR;
图8:不同浓度的LTK肽段刺激下JC5-TCR细胞的IL-2产量;
图9:LTK表位特异性TCR的EC50统计结果,其中public TCR代表CDR3基序保守的TCR;
图10:LSK特异TCR-T细胞与EBV-LCL细胞孵育后的IL2释放水平;
图11:LSK特异TCR-T细胞与EBV-LCL细胞孵育后的IFNγ释放水平;
图12:体外过量靶细胞长期刺激下TCR-T细胞的增殖结果图;
图13:体外过量靶细胞长期刺激下TCR-T细胞的杀伤能力检测图;
图14:BFP法测定public TCR的结构亲和力结果图;
图15:Alanine Scanning法分析E141-TCR CDR3区域各个氨基酸识别抗原并杀伤靶细胞能力的贡献;
图16:Alanine Scanning法分析E141-TCR CDR3区域各个氨基酸识别抗原并激活T细胞能力的贡献;
图17:淋巴瘤动物模型中评价E141-TCR在小鼠体内抑制肿瘤生长情况;
图18:实体瘤动物模型中评价E141-TCR在小鼠体内抑制肿瘤生长情况;
图19:实体瘤模型,无T细胞注射组(PBS)、对照TCR-T细胞注射组(TCR-1G4)、及EBVTCR-T注射组(E141-TCR)的小鼠肿瘤生长情况统计结果;
图20:实体瘤模型,无T细胞注射组(PBS)、对照TCR-T细胞注射组(TCR-1G4)、及EBVTCR-T注射组(E141-TCR)的小鼠体内TCR-T细胞特异增殖统计结果。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:EBV抗原表位四聚体的构建和效果检测
一、EBV抗原表位四聚体的构建
1)表达序列优化的HLA-A*1101(其氨基酸序列如SEQ ID NO:1所示,核苷酸序列如SEQ ID NO:2所示)的α链和β2m链(其氨基酸序列如SEQ ID NO:3所示,核苷酸序列如SEQ IDNO:4所示)。其中,α链的结构为相应HLA型α链的胞外区序列链接了Avi-tag序列,以BamHI酶切位点间隔,以提供生物素化的位点。β2m链去掉了信号肽序列,在成熟肽序列前面加了两个氨基酸(M和A)。表达载体为PET28a+,表达菌为transetta或BL21。IPTG浓度为0.5mM,诱导表达4h。提取α链和β2m链蛋白包涵体。
2)EBV抗原表位(抗原肽)的选择:HLA-A*1101型对应抗原表位SSCSSCPLSK(SEQ IDNO:5)、SSCSSCPLTK(SEQ ID NO:6)。
3)pMHC I单体折叠及纯化:将步骤2)所述抗原肽、相应的步骤1)所述β2m链复性蛋白和α链蛋白以摩尔比40:2:1的比例按顺序加入还原体系中,折叠反应72h。将得到的产物过Superdex75 10/300GL柱子纯化。收集纯化产物用avidity试剂盒生物素化,再次纯化得到生物素化的单体,凝胶电泳检测单体纯度。
4)将步骤3)所述生物素化的单体与APC标记的链霉亲和素结合反应,得到对应的四聚体,分别命名A1101–SSCSSCPLSK-四聚体及A1101-SSCSSCPLTK-四聚体。
二、EBV抗原表位四聚体效果检测
1.分离人外周血单核细胞(PBMC),制备细胞悬液,细胞密度为1×106细胞/mL。
2.将细胞离心,3000rpm,5min。去除上清,用50μl含有1%血清的PBS重悬。
3.加入2μl四聚体室温孵育30min。
4.加入2μl CD8抗体,冰上孵育20min。
5.加入1ml PBS,3000rpm,5min。
6.去除上清,加入1ml PBS,3000rpm,5min。
7.去除上清,用500μl的4%多聚甲醛重悬细胞,用滤膜过滤细胞悬液。
8.用流式细胞仪检测阳性细胞。
三、实验结果
单体的SDS PAGE检测结果见图1。如图所示,经复性折叠和HPLC纯化,得到的单体清晰地显示重链(C端连接Avi-tag序列的α链胞外区)和轻链(去除信号肽区的β2m链)对应大小的蛋白,且纯度较高。
将构建好的四聚体分别与感染了对应HLA型TCR的细胞共孵育。示例性的,构建的A1101-SSCSSCPLTK-四聚体、A1101-SSCSSCPLSK-四聚体分别与感染了对应HLA型TCR的细胞共孵育(LSK/LTK四聚体对应TCR E141),与MBL公司商业化四聚体相比,A1101-SSCSSCPLSK-四聚体检测阳性细胞百分比为20.3%,明显高于商业化的SSCSSCPLSK-四聚体(18.1%),如图2所示。充分表明本发明的四聚体在检测细胞阳性率方面表现了高度的特异性和染色效果。
通过本发明构建的四聚体所钓取的TCR能够同时识别野生型抗原表位和突变型抗原表位,防止免疫逃逸。如图3所示,A1101 HLA型野生型抗原表位(LSK)和突变型抗原表位(LTK)四聚体均能被由LSK四聚体钓取的TCR E141所识别。
实施例2:pHAGE-TCR-RFP载体的构建
一、获取EBV LMP2表位特异的TCR的β和α基因片段
1)取实施例1中制备的A1101–SSCSSCPLSK-四聚体及A1101-SSCSSCPLTK-四聚体,与外周血染色,将四聚体染色阳性的T细胞进行流式单细胞分选,反转录获得cDNA(IV Reverse Transcriptase,Invitrogen)。根据多重PCR(Multiplex PCR)原理,通过两轮PCR(KOD-Plus-Neo,TOYOBO)扩增出TCRβ基因的可变区片段。
反转录引物为:TRBC1-TCAGGCAGTATCTGGAGTCATTG(SEQ ID NO:227)
PCR扩增引物为:
上游引物1:TRBV_F1(SEQ ID NO:45至84,其中SEQ ID NO:48也可以单独分别作为制备E141、E149、E304、E314及E301的β基因的可变区片段的TRBV_F1,SEQ ID NO:62也可以单独作为制备E254的β基因的可变区片段的TRBV_F1)
上游引物2:TRBV_F2(SEQ ID NO:85至124,其中SEQ ID NO:88也可以单独分别作为制备E141、E149、E304、E314及E301的β基因的可变区片段的TRBV_F2,SEQ ID NO:104也可以单独作为制备E254的β基因的可变区片段的TRBV_F2)
下游引物1:TRBC2-GCACCTCCTTCCCATTCACC(SEQ ID NO:228)
下游引物2:TRBC3-GCTTCTGATGGCTCAAACACAG(SEQ ID NO:229)
具体的,根据PCR聚合酶KOD-Plus-Neo产品说明书,一轮PCR体系为20μL,退火温度为60℃,反应30个循环。取第一轮PCR反应的产物1μL,作为二轮PCR的模板,二轮PCR体系为30μL,退火温度为60℃,反应30个循环。然后将第二轮PCR产物跑琼脂糖胶,将对应大小的条带进行切胶回收(天根胶回收试剂盒),送测序,测序引物为下游引物2。得到TCRβ基因序列,具体的E141、E149、E254、E304、E314、E301的TCRβ基因序列分别如SEQ ID NO:7-12所示核苷酸序列。
2)如上,对四聚体染色阳性T细胞的进行反转录获得cDNA(IVReverse Transcriptase,Invitrogen)。根据产品说明书通过两轮PCR(KOD-Plus-Neo,TOYOBO)扩增出TCRα基因片段。
反转录引物为:TRAC1-CGACCAGCTTGACATCACAG(SEQ ID NO:230)
PCR扩增引物为:
上游引物3:TRAV_F1(SEQ ID NO:125至169,其中SEQ ID NO:152也可以单独作为制备E141、E149、E254、E304、E314及E301的α基因的可变区片段的TRAV_F1)
上游引物4:TRAV_F2(SEQ ID NO:170至211,其中SEQ ID NO:195也可以单独作为制备E141、E149、E254、E304、E314及E301的α基因的可变区片段的TRAV_F2)
下游引物3:TRAC2-GTTGCTCTTGAAGTCCATAGACCTC(SEQ ID NO:231)下游引物4:TRAC3-CAGGGTCAGGGTTCTGGATA(SEQ ID NO:232)
具体的,根据PCR聚合酶KOD-Plus-Neo产品说明书,一轮PCR体系为20μL,退火温度为60℃,反应30个循环。取第一轮PCR反应的产物1μL,作为二轮PCR的模板,二轮PCR体系为30μL,退火温度为60℃,反应30个循环。然后将第二轮PCR产物跑琼脂糖胶,将对应大小的条带进行切胶回收(天根胶回收试剂盒),送测序,测序引物为下游引物4。得到TCRα基因序列,具体的E141、E149、E254、E304、E314、E301的TCRα基因序列分别如SEQ ID NO:13-18所示核苷酸序列。
二、pHAGE-TCR载体的构建
将TCRβ,fp2A,TCRα经长引物(包含fp2A序列)overlap-PCR扩增(KOD-Plus-Neo,TOYOBO)得到TCRβ-fp2A-TCRα片段,分别命名为E141、E149、E254、E304、E314、E301的pHAGE-TCR质粒。
扩增的引物为:
上游引物5见SEQ ID NO:233至238。
下游引物5:
TCTCCAGCCTGCTTCAGCAGGCTGAAGTTAGTAGCTCCGCTTCCGCTccgtttccgccgGAAATCCTTTCTCTTGACCATG(SEQ ID NO:239)
上游引物6见SEQ ID NO:240至245。
下游引物6:agggatcctctagactcgagctagcTCAGCTGGACCACAGCCGCA(SEQ ID NO:246)
具体的,先用引物5和引物6分别将TCRβ和TCRα扩增出来,PCR体系为50μL,退火温度为60℃,反应30个循环。将PCR产物跑胶回收(天根胶回收试剂盒),分别取回收产物1μL作为模板,用上游引物5和下游引物6进行overlap PCR,PCR体系为50μL,退火温度为60℃,反应30个循环。跑琼脂糖胶得到约1800bp的条带,进行切胶回收。
将慢病毒载体pHAGE-IRES-RFP用NotI和NheI进行双酶切。酶切体系为40μL,其中含NotI和NheI分别1.5μL,质粒2-3μg,37℃酶切6h,然后在体系里加入1μL碱性磷酸酶(NEB),处理1h以减少质粒自连,将酶切后的质粒跑胶回收,用nanodrop测浓度,作为骨架用于构建质粒。
根据Clone Express II One Step Cloning kit产品说明书,将TCR通过overlap与酶切后线性化的pHAGE-IRES-RFP载体进行连接(见图4),转化至Stbl3菌株,在含氨苄的LB平板上培养12-16h,挑取单克隆菌进行测序,测序引物选用pHAGE载体上的引物seq-pHAGE-F和seq-pHAGE-R,以及下游引物4。获得相应TCR,简称分别为E141、E149、E254、E304、E314、E301。
实施例3:pMHC四聚体染色法检测TCR的膜表达和亲和力
1、构建内源性TCR敲除的JurkatT细胞系
基于Jurkat细胞TCR的序列特征,在α链和β链的恒定区设计guide序列(TRA_oligo1-CACCGTCTCTCAGCTGGTACACGGC(SEQIDNO:247),TRA_oligo2-AAACGCCGTGTACCAGCTGAGAGAC(SEQIDNO:248),TRB_oligo1-CACCGGGCTCAAACACAGCGACCTC(SEQIDNO:249),TRB_oligo2-AAACGAGGTCGCTGTGTTTGAGCCC)(SEQIDNO:250)。
将合成的α链和β链的guide序列分别构建到sgRNA-LentiCRISPR-puro和sgRNA-LentiCRISPR-BSD慢病毒载体中,与包装质粒psPAX2,pMD2.G和PEI转染试剂按照一定的比例共转293T细胞,收取48h和72h的细胞培养上清,浓缩后的两个病毒同时感染人类JurkatT细胞系。感染48h后用合适浓度的嘌呤霉素和杀稻瘟菌素进行药杀,直至两个药物各自的对照组细胞全部死亡。存活的细胞用流式分选单细胞到96孔板中进行培养。对于获得的单克隆细胞系,用TCRα链和β链的抗体分别对其表达进行鉴定,两条链都缺陷的细胞株即为获得的内源性TCR敲除的Jurkat T细胞,命名为JC5。
2、构建稳定整合EBV TCR的JC5细胞系
将实施例2构建的上述E141、E149、E254、E304、E314、E301的pHAGE-TCR质粒分别与包装质粒psPAX2,pMD2.G以及转染试剂PEI按照一定的比例混合,转染293T细胞。收取48h和72h的细胞培养上清,浓缩后感染对数生长期的JC5细胞(MOI=0.3)。感染3天后,用抗人CD3和抗人TCRαβ流式抗体对细胞进行染色,将相同TCR表达水平的细胞分选后进行培养,即为JC5-TCR细胞系。
3、TCR上膜情况及亲和力检测
取1×106JC5-TCR细胞,用Brilliant Violet 421TM anti-human TCRαβ(Biolegend)以及相应的EBV LMP2 pMHC四聚体-APC(Tetramer-APC)染色,之后进行流式分析。
由图5可知,所制备的针对EBV LMP2 HLA-A*A1101 SSCSSCPLSK/SSCSSCPLTK的特异TCR中,构建的TCR均对SSCSSCPLSK/SSCSSCPLTK表位有较好的结合。这一结果不仅表明了自制四聚体能成功的用于鉴定特异结合的T细胞,并且表明所获得的TCR具有良好的亲和力。
实施例4:TCR功能活性和EC50
鉴于实施例3中pMHC四聚体检测的是TCR的结构亲和能力,并且四聚体与JC5表面的TCR是四价结合。为进一步鉴定TCR的活性,我们在T2细胞中稳定整合了HLA-A*1101分子,构建了T2-HLA-A*1101细胞系用于定量TCR的半最大效应抗原浓度(EC50),比较TCR的功能活性。
1、构建稳定整合HLA-A*1101的T2细胞系
克隆HLA-A*1101分子和β2m分子(来源于人),用fp2A连接后构建到pHAGE-BSD载体中,与包装质粒psPAX2,pMD2.G和PEI转染试剂(由实施例2制备)按照一定的比例共转293T细胞进行包毒,用于感染T2细胞系。感染48h的T2细胞用合适浓度的杀稻瘟菌素进行药杀,直至对照组细胞全部死亡,获得T2-HLA-A*1101细胞系。
2、TCR功能活性和EC50的测定
将合成的LMP2抗原表位用DMSO溶剂稀释到4mg/mL的储存浓度。然后用完全培养基对表位肽段进行连续梯度稀释,获得2×10-8-2×10-4M的LSK和LTK肽段溶液,以1:100的体积添加到1×106细胞/mL的T2-HLA-A*1101细胞悬液中,混匀后将细胞铺在96孔板中,每孔100μL,同时加入100μL浓度为1×106细胞/mL的JC5-TCR细胞,混匀后即为肽段浓度是1×10-10-1×10-6M的T2孵育体系。共培养24h后,收集培养基上清,用ELISA试剂盒检测IL2产量。实验重复三次。图6和图8分别代表了不同浓度的LSK和LTK肽段刺激下JC5-TCR细胞的IL2产量。相应的EC50值可以通过prism计算获得,三次重复的EC50值具体如图7和图9。由图6-9可知,对于合成的LSK抗原表位以及LTK表位,各TCR都展现了较好的功能活性。
实施例5:人原代TCR-T细胞的构建及体外功能检测
1、人类原代T细胞的分离、培养和慢病毒感染
为了进一步验证所筛选到的TCR对EBV LMP2抗原的识别和杀伤功能,采用淋巴细胞分离液Ficoll从志愿者的外周血中分离得到单个核细胞(PBMC),然后根据EasySepHuman T cell isolation kit(stem cell technologies)产品说明书,从PBMC中通过阴选的方法获得T细胞,用含有100U/mL IL2的1640完全培养基将细胞重悬至1×106细胞/mL,培养在抗CD3/CD28抗体包被的培养皿中进行激活。激活48h后,用慢病毒体系将装载有TCR的病毒颗粒(由实施例2制备)感染T细胞,感染方法为32℃下1500rpm离心2h,取出后放在37℃细胞培养箱培养10h,然后通过添换培养基终止感染,并继续放在37℃细胞培养箱进行培养。感染三天后可用流式细胞仪将TCR阳性的细胞分选出来,获得TCR-T细胞(包括上述E141、E149、E254、E304、E314、E301)。
2、靶细胞的构建
用慢病毒体系将分别装载有LMP2-RFP、HLA-A*1101-BSD以及Luciferase-GFP的病毒颗粒感染对数生长期的Raji细胞。通过药物筛选及流式分选,得到同时稳定表达LMP2、HLA-A分子以及Luciferas-GFP的Raji细胞,命名为Raji-1101-LMP2-luciferase。此外,将HLA-A*1101-BSD的病毒颗粒感染对数生长期的EBV-LCL细胞。通过药物筛选,得到稳定表达HLA-A分子的EBV-LCL细胞,命名为EBV-LCL-HLA-A*1101细胞。
3、TCR在人原代T细胞中的体外功能验证
1)验证TCR对内源水平抗原表位的识别能力
EBV-LCL即为被EB病毒侵染后永生化的人B细胞,较为真实的模拟了体内肿瘤细胞中的抗原水平。因此,将识别SSCSSCPLSK/SSCSSCPLTK表位的TCR-T细胞和EBV-LCL-HLA-A*1101细胞按照效靶比为8:1、4:1、2:1、1:1、0.5:1、0.25:1进行共培养,其中靶细胞固定为1×105细胞。共孵育24h后,收集上清用于检测分泌的细胞因子IL2(图10)和IFN-γ(图11)。从细胞因子释放水平来看,TCR:E141,E254结合内源水平的LSK后可以显著地激活T细胞,结果表明本发明制备的TCR能有效介导肿瘤内源抗原的识别。
2)验证TCR-T细胞对肿瘤细胞的长期杀伤能力
将识别SSCSSCPLSK/SSCSSCPLTK表位的TCR-T细胞和Raji-HLA-A*1101-LMP2-luciferase细胞按照效靶比为1:3进行起始共培养,记为0天,然后分别在1天,3天,5天收集细胞进行流式分析。其中,所用培养基为不含IL2的1640完全培养基,起始的TCR-T细胞为1×105细胞,各个时间点的样品独立孵育,并分别在2天,4天的时候对剩余的共孵育样品进行半换液,补加靶细胞。用于流式分析的细胞先用抗人CD3抗体进行染色,上机时收集记录指定体积的细胞,通过换算得知体系里T细胞的数量(见图12)。由绝对T细胞数量的增殖曲线可见,E141-TCR-T和E304-TCR-T细胞在识别两个抗原表位后进行了很好的激活和增殖。此外,进一步分析体系里的效靶比例(见图13),与增殖结果相同,E141-TCR-T和E304-TCR-T细胞展现了最强的肿瘤清除能力。
实施例6:共享CDR3基序的TCR功能比较
由于鉴定到的识别SSCSSCPLSK/SSCSSCPLTK表位的E141、E149、E254、E301、E304以及E314在TCRα链和β链的CDR3高变区均非常保守,序列高度相似至相差一个氨基酸但是功能上相去甚远(图7和图9)。因此将具有这些保守CDR3基序的TCR定义为public TCR。并在此实施例中对public TCR的结构亲和力和功能进行分析。
1、BFP法测定public TCR的结构亲和力
将红细胞固定在一侧的微量吸液管上,然后将特异包埋有pMHC分子的珠子吸附在红细胞表面,形成超敏的生物膜力学探针(BFP),同时将JCR-TCR细胞固定在另一侧的微量吸液管上,通过压电式传感器控制两者的接触,每个循环接触时外加压力为10pN,接触时间为0.1s,然后以1000pN/s的速度分开,进行下一个循环重复。整个过程用显微镜记录红细胞-珠子表面的形变,判断是否有键形成以及持续时间。由图14的成键持续时间可知,public TCR之间对LSK表位的结构亲和力参差不齐,其中E304具有较好的功能,与T2的结果吻合(图7)。
2、Alanine Scanning法分析保守的CDR3基序的功能
将TCR E141α链和β链CDR3区域首位后的氨基酸依次突变成丙氨酸,命名为a2-a9以及b2-b11,构建到pHAGE慢病毒载体中,包毒后感染人原代T细胞(MOI=10),感染三天后可用流式细胞仪将TCR阳性的细胞分选出来。分选后的TCR-T细胞和Raji-LMP2-luciferase靶细胞按照效靶比为1:1进行共培养,其中T细胞为1×105细胞。共孵育24h后,分别收集细胞和上清,细胞沉淀裂解后用于检测尚存活靶细胞释放的荧光素酶量(图15),上清用于检测TCR-T细胞分泌的细胞因子IL2(图16)。根据图15和图16可知,与HLA unmatched-Raji细胞、或未添加TCR-T细胞以及添加了未转染TCR的pan-T细胞的HLA matched-Raji这些对照组的本底值相比,未突变的E141遇到HLA matched-Raji后能有效的清除靶细胞,并且特异的产生大量的细胞因子IL2。但是,在a3、a5、a6以及b6、b7、b8这些位点,单个氨基酸的突变足以让TCR-T细胞彻底失活。这些实验结果共同表明,尽管这些public TCR共享同一个保守的基序,相互之间的功能可能会因为一个氨基酸的差异而相去甚远。
实施例7:动物模型构建及EBV TCR-T体内功能检测
EB病毒主要感染鼻咽上皮细胞和B细胞,与鼻咽癌和多种B细胞淋巴瘤的发生发展密切相关。本实施例分别构建了B细胞淋巴瘤小鼠模型和鼻咽癌实体瘤模型,以验证所鉴定的TCR的体内功能。
1、淋巴瘤模型及TCR-T体内功能检测
将3×105Raji-HLA-A*1101-LMP2-luciferase肿瘤细胞通过尾静脉接种给5-6周的NOD/Scid IL-2Rγnull(NCG)雌鼠,构建淋巴瘤模型(见图17),记为第1天,第5天时,将小鼠分为3个小组,分别为A:PBS注射组(注射等体积PBS);B:对照TCR-T细胞注射组(TCR-1G4T细胞);C:EBV TCR-T注射组(E141-TCR-T细胞),B/C组小鼠尾静脉注射5×106TCR-T细胞,A组注射等体积200μL PBS。第8天时进行二次注射,具体操作与第5天一致。在接下来的几周监测小鼠体内肿瘤细胞生长情况,T细胞体内增殖情况以及小鼠存活情况。如图17所示,与对照组比较,本发明实施例构建的EBV特异性E141-TCR-T细胞能够显著地杀伤小鼠体内肿瘤细胞,提高小鼠的存活率。
2、实体瘤模型
将1×106C666-1-HLA-A*1101-LMP2-luciferase肿瘤细胞通过皮下接种给5-6周的NCG雌鼠,构建鼻咽癌实体瘤模型(见图18),记为第0天,7天后,将小鼠分为3个小组,分别为A:PBS注射组(注射等体积PBS);B:对照TCR-T细胞注射组(TCR-1G4 T细胞);C:EBV TCR-T注射组(E141-TCR-T细胞),B/C组小鼠尾静脉注射3×106T细胞,A组注射等体积200μL PBS。在接下来的几周监测小鼠体内肿瘤细胞生长情况,T细胞体内增殖情况以及小鼠存活情况。如图18,图19以及图20所示,与对照组比较,本发明实施例构建的EBV特异性E141-TCR-T细胞能够显著地杀伤小鼠体内肿瘤细胞(图18,图19),并且回输的TCR-T细胞在体内进行了特异的增殖(图20)。
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
序列表
<110> 华夏英泰(北京)生物技术有限公司、清华大学
<120> 一种T细胞抗原受体、其多聚体复合物及其制备方法和应用
<130> 1
<160> 251
<170> SIPOSequenceListing 1.0
<210> 1
<211> 294
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Gly Ser His Ser Met Arg Tyr Phe Tyr Thr Ser Val Ser Arg Pro
1 5 10 15
Gly Arg Gly Glu Pro Arg Phe Ile Ala Val Gly Tyr Val Asp Asp Thr
20 25 30
Gln Phe Val Arg Phe Asp Ser Asp Ala Ala Ser Gln Arg Met Glu Pro
35 40 45
Arg Ala Pro Trp Ile Glu Gln Glu Gly Pro Glu Tyr Trp Asp Gln Glu
50 55 60
Thr Arg Asn Val Lys Ala Gln Ser Gln Thr Asp Arg Val Asp Leu Gly
65 70 75 80
Thr Leu Arg Gly Tyr Tyr Asn Gln Ser Glu Asp Gly Ser His Thr Ile
85 90 95
Gln Ile Met Tyr Gly Cys Asp Val Gly Pro Asp Gly Arg Phe Leu Arg
100 105 110
Gly Tyr Arg Gln Asp Ala Tyr Asp Gly Lys Asp Tyr Ile Ala Leu Asn
115 120 125
Glu Asp Leu Arg Ser Trp Thr Ala Ala Asp Met Ala Ala Gln Ile Thr
130 135 140
Lys Arg Lys Trp Glu Ala Ala His Ala Ala Glu Gln Gln Arg Ala Tyr
145 150 155 160
Leu Glu Gly Arg Cys Val Glu Trp Leu Arg Arg Tyr Leu Glu Asn Gly
165 170 175
Lys Glu Thr Leu Gln Arg Thr Asp Pro Pro Lys Thr His Met Thr His
180 185 190
His Pro Ile Ser Asp His Glu Ala Thr Leu Arg Cys Trp Ala Leu Gly
195 200 205
Phe Tyr Pro Ala Glu Ile Thr Leu Thr Trp Gln Arg Asp Gly Glu Asp
210 215 220
Gln Thr Gln Asp Thr Glu Leu Val Glu Thr Arg Pro Ala Gly Asp Gly
225 230 235 240
Thr Phe Gln Lys Trp Val Ala Val Val Val Pro Ser Gly Glu Glu Gln
245 250 255
Arg Tyr Thr Cys His Val Gln His Glu Gly Leu Pro Lys Pro Leu Thr
260 265 270
Leu Arg Trp Glu Leu Gly Ser Gly Leu Asn Asp Ile Phe Glu Ala Gln
275 280 285
Lys Ile Glu Trp His Glu
290
<210> 2
<211> 885
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
atgggtagcc atagcatgcg ctacttctat accagcgtga gtcgtccggg ccgtggtgaa 60
cctcgcttta ttgccgtggg ctatgtggat gacacccagt tcgtgcgctt tgatagcgat 120
gccgcaagtc agcgcatgga accgcgtgcc ccgtggattg aacaagaagg cccggaatat 180
tgggaccaag aaacacgcaa cgttaaggcc cagagccaga cagatcgtgt ggatctgggt 240
acactgcgcg gctattacaa tcagagcgag gatggcagcc acaccattca gatcatgtac 300
ggctgcgatg ttggtccgga cggtcgcttt ttacgtggct accgtcaaga tgcctatgat 360
ggcaaggact atatcgcttt aaacgaggat ctgcgcagtt ggaccgcagc cgatatggcc 420
gcacagatca ccaaacgcaa atgggaagca gcacacgccg ccgagcagca acgtgcatat 480
ttagaaggtc gttgcgtgga atggctgcgc cgctatctgg agaatggcaa agaaacttta 540
cagcgtaccg atccgccgaa aacccatatg acccatcacc cgatcagcga tcatgaggcc 600
actttacgtt gttgggcact gggcttttat ccggcagaaa tcactttaac ttggcagcgc 660
gatggtgaag atcagaccca agataccgaa ctggtggaaa cccgccccgc tggtgatggc 720
acctttcaga aatgggttgc agtggttgtg ccgagcggcg aggaacagcg ttacacttgt 780
cacgttcagc atgaaggttt accgaaaccg ctgactttac gttgggaact gggatccggt 840
ttgaacgaca tcttcgaagc tcagaaaatc gaatggcacg aataa 885
<210> 3
<211> 101
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 3
Met Ala Ile Gln Arg Thr Pro Lys Ile Gln Val Tyr Ser Arg His Pro
1 5 10 15
Ala Glu Asn Gly Lys Ser Asn Phe Leu Asn Cys Tyr Val Ser Gly Phe
20 25 30
His Pro Ser Asp Ile Glu Val Asp Leu Leu Lys Asn Gly Glu Arg Ile
35 40 45
Glu Lys Val Glu His Ser Asp Leu Ser Phe Ser Lys Asp Trp Ser Phe
50 55 60
Tyr Leu Leu Tyr Tyr Thr Glu Phe Thr Pro Thr Glu Lys Asp Glu Tyr
65 70 75 80
Ala Cys Arg Val Asn His Val Thr Leu Ser Gln Pro Lys Ile Val Lys
85 90 95
Trp Asp Arg Asp Met
100
<210> 4
<211> 306
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
atggcaatcc agcgtactcc aaagattcag gtttactcac gtcatccagc agagaatgga 60
aagtcaaatt tcctgaattg ctatgtgtct gggtttcatc catccgacat tgaagttgac 120
ttactgaaga atggagagag aattgaaaaa gtggagcatt cagacttgtc tttcagcaag 180
gactggtctt tctatctctt gtactacact gaattcaccc ccactgaaaa agatgagtat 240
gcctgccgtg tgaaccatgt gactttgtca cagcccaaga tagttaagtg ggatcgagac 300
atgtaa 306
<210> 5
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Ser Ser Cys Ser Ser Cys Pro Leu Ser Lys
1 5 10
<210> 6
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Ser Ser Cys Ser Ser Cys Pro Leu Thr Lys
1 5 10
<210> 7
<211> 924
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 7
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc aggggcgatg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttc 924
<210> 8
<211> 924
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc ccgggaggtg gtatgagcag 360
ttcttcgggc cagggacacg gctcaccgtg ctagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttc 924
<210> 9
<211> 924
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
atgggcttca ggctcctctg ctgtgtggcc ttttgtctcc tgggagcagg cccagtggat 60
tctggagtca cacaaacccc aaagcacctg atcacagcaa ctggacagcg agtgacgctg 120
agatgctccc ctaggtctgg agacctctct gtgtactggt accaacagag cctggaccag 180
ggcctccagt tcctcattca gtattataat ggagaagaga gagcaaaagg aaacattctt 240
gaacgattct ccgcacaaca gttccctgac ttgcactctg aactaaacct gagctctctg 300
gagctggggg actcagcttt gtatttctgt gccagcagcg taggtccatg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttc 924
<210> 10
<211> 924
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc cggggcggtg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttc 924
<210> 11
<211> 924
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc aagggcggtg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttc 924
<210> 12
<211> 924
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc ccgggcgatt ctacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttc 924
<210> 13
<211> 807
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
atgaagagga tattgggagc tctgctgggg ctcttgagtg cccaggtttg ctgtgtgaga 60
ggaatacaag tggagcagag tcctccagac ctgattctcc aggagggagc caattccacg 120
ctgcggtgca atttttctga ctctgtgaac aatttgcagt ggtttcatca aaacccttgg 180
ggacagctca tcaacctgtt ttacattccc tcagggacaa aacagaatgg aagattaagc 240
gccacgactg tcgctacgga acgctacagc ttattgtaca tttcctcttc ccagaccaca 300
gactcaggcg tttatttctg tgctgttcta aataacaatg acatgcgctt tggagcaggg 360
accagactga cagtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 420
gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 480
gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 540
tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 600
gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 660
tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 720
aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 780
atgacgctgc ggctgtggtc cagctga 807
<210> 14
<211> 807
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
atgaagagga tattgggagc tctgctgggg ctcttgagtg cccaggtttg ctgtgtgaga 60
ggaatacaag tggagcagag tcctccagac ctgattctcc aggagggagc caattccacg 120
ctgcggtgca atttttctga ctctgtgaac aatttgcagt ggtttcatca aaacccttgg 180
ggacagctca tcaacctgtt ttacattccc tcagggacaa aacagaatgg aagattaagc 240
gccacgactg tcgctacgga acgctacagc ttattgtaca tttcctcttc ccagaccaca 300
gactcaggcg tttatttctg tgctgtggtc gataacaatg acatgcgctt tggagcaggg 360
accagactga cagtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 420
gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 480
gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 540
tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 600
gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 660
tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 720
aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 780
atgacgctgc ggctgtggtc cagctga 807
<210> 15
<211> 807
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
atgaagagga tattgggagc tctgctgggg ctcttgagtg cccaggtttg ctgtgtgaga 60
ggaatacaag tggagcagag tcctccagac ctgattctcc aggagggagc caattccacg 120
ctgcggtgca atttttctga ctctgtgaac aatttgcagt ggtttcatca aaacccttgg 180
ggacagctca tcaacctgtt ttacattccc tcagggacaa aacagaatgg aagattaagc 240
gccacgactg tcgctacgga acgctacagc ttattgtaca tttcctcttc ccagaccaca 300
gactcaggcg tttatttctg tgctgtgcta aataacaatg acatgcgctt tggagcaggg 360
accagactga cagtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 420
gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 480
gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 540
tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 600
gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 660
tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 720
aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 780
atgacgctgc ggctgtggtc cagctga 807
<210> 16
<211> 807
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
atgaagagga tattgggagc tctgctgggg ctcttgagtg cccaggtttg ctgtgtgaga 60
ggaatacaag tggagcagag tcctccagac ctgattctcc aggagggagc caattccacg 120
ctgcggtgca atttttctga ctctgtgaac aatttgcagt ggtttcatca aaacccttgg 180
ggacagctca tcaacctgtt ttacattccc tcagggacaa aacagaatgg aagattaagc 240
gccacgactg tcgctacgga acgctacagc ttattgtaca tttcctcttc ccagaccaca 300
gactcaggcg tttatttctg tgctgtggtc gataacaatg acatgcgctt tggagcaggg 360
accagactga cagtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 420
gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 480
gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 540
tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 600
gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 660
tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 720
aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 780
atgacgctgc ggctgtggtc cagctga 807
<210> 17
<211> 807
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
atgaagagga tattgggagc tctgctgggg ctcttgagtg cccaggtttg ctgtgtgaga 60
ggaatacaag tggagcagag tcctccagac ctgattctcc aggagggagc caattccacg 120
ctgcggtgca atttttctga ctctgtgaac aatttgcagt ggtttcatca aaacccttgg 180
ggacagctca tcaacctgtt ttacattccc tcagggacaa aacagaatgg aagattaagc 240
gccacgactg tcgctacgga acgctacagc ttattgtaca tttcctcttc ccagaccaca 300
gactcaggcg tttatttctg tgctgtgcta gataacaatg acatgcgctt tggagcaggg 360
accagactga cagtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 420
gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 480
gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 540
tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 600
gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 660
tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 720
aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 780
atgacgctgc ggctgtggtc cagctga 807
<210> 18
<211> 807
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
atgaagagga tattgggagc tctgctgggg ctcttgagtg cccaggtttg ctgtgtgaga 60
ggaatacaag tggagcagag tcctccagac ctgattctcc aggagggagc caattccacg 120
ctgcggtgca atttttctga ctctgtgaac aatttgcagt ggtttcatca aaacccttgg 180
ggacagctca tcaacctgtt ttacattccc tcagggacaa aacagaatgg aagattaagc 240
gccacgactg tcgctacgga acgctacagc ttattgtaca tttcctcttc ccagaccaca 300
gactcaggcg tttatttctg tgctgtcctt aataacaatg acatgcgctt tggagcaggg 360
accagactga cagtaaaacc aaatatccag aaccctgacc ctgccgtgta ccagctgaga 420
gactctaaat ccagtgacaa gtctgtctgc ctattcaccg attttgattc tcaaacaaat 480
gtgtcacaaa gtaaggattc tgatgtgtat atcacagaca aaactgtgct agacatgagg 540
tctatggact tcaagagcaa cagtgctgtg gcctggagca acaaatctga ctttgcatgt 600
gcaaacgcct tcaacaacag cattattcca gaagacacct tcttccccag cccagaaagt 660
tcctgtgatg tcaagctggt cgagaaaagc tttgaaacag atacgaacct aaactttcaa 720
aacctgtcag tgattgggtt ccgaatcctc ctcctgaaag tggccgggtt taatctgctc 780
atgacgctgc ggctgtggtc cagctga 807
<210> 19
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gln Gly Arg Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val Cys
340 345 350
Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu
355 360 365
Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val
370 375 380
Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn
385 390 395 400
Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala
405 410 415
Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser
420 425 430
Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asn Asn Asn
435 440 445
Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 20
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 20
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Gly Arg Trp Tyr Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val Cys
340 345 350
Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu
355 360 365
Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val
370 375 380
Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn
385 390 395 400
Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala
405 410 415
Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser
420 425 430
Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Val Asp Asn Asn
435 440 445
Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 21
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 21
Met Gly Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Val Gly Pro Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val Cys
340 345 350
Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu
355 360 365
Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val
370 375 380
Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn
385 390 395 400
Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala
405 410 415
Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser
420 425 430
Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asn Asn Asn
435 440 445
Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 22
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Gly Arg Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val Cys
340 345 350
Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu
355 360 365
Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val
370 375 380
Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn
385 390 395 400
Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala
405 410 415
Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser
420 425 430
Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Val Asp Asn Asn
435 440 445
Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 23
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gln Gly Arg Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val Cys
340 345 350
Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu
355 360 365
Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val
370 375 380
Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn
385 390 395 400
Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala
405 410 415
Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser
420 425 430
Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asp Asn Asn
435 440 445
Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 24
<211> 603
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Gly Arg Phe Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe
305 310 315 320
Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met
325 330 335
Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val Cys
340 345 350
Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile Leu
355 360 365
Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser Val
370 375 380
Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile Asn
385 390 395 400
Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser Ala
405 410 415
Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser Ser
420 425 430
Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asn Asn Asn
435 440 445
Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn Ile
450 455 460
Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser Ser
465 470 475 480
Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn Val
485 490 495
Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val Leu
500 505 510
Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp Ser
515 520 525
Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile Ile
530 535 540
Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val Lys
545 550 555 560
Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln Asn
565 570 575
Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly Phe
580 585 590
Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
595 600
<210> 25
<211> 308
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gln Gly Arg Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 26
<211> 308
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Gly Arg Trp Tyr Glu Gln Phe Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Leu Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 27
<211> 308
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Met Gly Phe Arg Leu Leu Cys Cys Val Ala Phe Cys Leu Leu Gly Ala
1 5 10 15
Gly Pro Val Asp Ser Gly Val Thr Gln Thr Pro Lys His Leu Ile Thr
20 25 30
Ala Thr Gly Gln Arg Val Thr Leu Arg Cys Ser Pro Arg Ser Gly Asp
35 40 45
Leu Ser Val Tyr Trp Tyr Gln Gln Ser Leu Asp Gln Gly Leu Gln Phe
50 55 60
Leu Ile Gln Tyr Tyr Asn Gly Glu Glu Arg Ala Lys Gly Asn Ile Leu
65 70 75 80
Glu Arg Phe Ser Ala Gln Gln Phe Pro Asp Leu His Ser Glu Leu Asn
85 90 95
Leu Ser Ser Leu Glu Leu Gly Asp Ser Ala Leu Tyr Phe Cys Ala Ser
100 105 110
Ser Val Gly Pro Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 28
<211> 308
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Gly Arg Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 29
<211> 308
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Gln Gly Arg Trp Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 30
<211> 308
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Met Gly Cys Arg Leu Leu Cys Cys Ala Val Leu Cys Leu Leu Gly Ala
1 5 10 15
Val Pro Ile Asp Thr Glu Val Thr Gln Thr Pro Lys His Leu Val Met
20 25 30
Gly Met Thr Asn Lys Lys Ser Leu Lys Cys Glu Gln His Met Gly His
35 40 45
Arg Ala Met Tyr Trp Tyr Lys Gln Lys Ala Lys Lys Pro Pro Glu Leu
50 55 60
Met Phe Val Tyr Ser Tyr Glu Lys Leu Ser Ile Asn Glu Ser Val Pro
65 70 75 80
Ser Arg Phe Ser Pro Glu Cys Pro Asn Ser Ser Leu Leu Asn Leu His
85 90 95
Leu His Ala Leu Gln Pro Glu Asp Ser Ala Leu Tyr Leu Cys Ala Ser
100 105 110
Ser Pro Gly Arg Phe Tyr Glu Gln Tyr Phe Gly Pro Gly Thr Arg Leu
115 120 125
Thr Val Thr Glu Asp Leu Lys Asn Val Phe Pro Pro Glu Val Ala Val
130 135 140
Phe Glu Pro Ser Glu Ala Glu Ile Ser His Thr Gln Lys Ala Thr Leu
145 150 155 160
Val Cys Leu Ala Thr Gly Phe Phe Pro Asp His Val Glu Leu Ser Trp
165 170 175
Trp Val Asn Gly Lys Glu Val His Ser Gly Val Ser Thr Asp Pro Gln
180 185 190
Pro Leu Lys Glu Gln Pro Ala Leu Asn Asp Ser Arg Tyr Cys Leu Ser
195 200 205
Ser Arg Leu Arg Val Ser Ala Thr Phe Trp Gln Asn Pro Arg Asn His
210 215 220
Phe Arg Cys Gln Val Gln Phe Tyr Gly Leu Ser Glu Asn Asp Glu Trp
225 230 235 240
Thr Gln Asp Arg Ala Lys Pro Val Thr Gln Ile Val Ser Ala Glu Ala
245 250 255
Trp Gly Arg Ala Asp Cys Gly Phe Thr Ser Val Ser Tyr Gln Gln Gly
260 265 270
Val Leu Ser Ala Thr Ile Leu Tyr Glu Ile Leu Leu Gly Lys Ala Thr
275 280 285
Leu Tyr Ala Val Leu Val Ser Ala Leu Val Leu Met Ala Met Val Lys
290 295 300
Arg Lys Asp Phe
305
<210> 31
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asn Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 32
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Val Asp Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 33
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asn Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 34
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Val Asp Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 35
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asp Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 36
<211> 268
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Met Lys Arg Ile Leu Gly Ala Leu Leu Gly Leu Leu Ser Ala Gln Val
1 5 10 15
Cys Cys Val Arg Gly Ile Gln Val Glu Gln Ser Pro Pro Asp Leu Ile
20 25 30
Leu Gln Glu Gly Ala Asn Ser Thr Leu Arg Cys Asn Phe Ser Asp Ser
35 40 45
Val Asn Asn Leu Gln Trp Phe His Gln Asn Pro Trp Gly Gln Leu Ile
50 55 60
Asn Leu Phe Tyr Ile Pro Ser Gly Thr Lys Gln Asn Gly Arg Leu Ser
65 70 75 80
Ala Thr Thr Val Ala Thr Glu Arg Tyr Ser Leu Leu Tyr Ile Ser Ser
85 90 95
Ser Gln Thr Thr Asp Ser Gly Val Tyr Phe Cys Ala Val Leu Asn Asn
100 105 110
Asn Asp Met Arg Phe Gly Ala Gly Thr Arg Leu Thr Val Lys Pro Asn
115 120 125
Ile Gln Asn Pro Asp Pro Ala Val Tyr Gln Leu Arg Asp Ser Lys Ser
130 135 140
Ser Asp Lys Ser Val Cys Leu Phe Thr Asp Phe Asp Ser Gln Thr Asn
145 150 155 160
Val Ser Gln Ser Lys Asp Ser Asp Val Tyr Ile Thr Asp Lys Thr Val
165 170 175
Leu Asp Met Arg Ser Met Asp Phe Lys Ser Asn Ser Ala Val Ala Trp
180 185 190
Ser Asn Lys Ser Asp Phe Ala Cys Ala Asn Ala Phe Asn Asn Ser Ile
195 200 205
Ile Pro Glu Asp Thr Phe Phe Pro Ser Pro Glu Ser Ser Cys Asp Val
210 215 220
Lys Leu Val Glu Lys Ser Phe Glu Thr Asp Thr Asn Leu Asn Phe Gln
225 230 235 240
Asn Leu Ser Val Ile Gly Phe Arg Ile Leu Leu Leu Lys Val Ala Gly
245 250 255
Phe Asn Leu Leu Met Thr Leu Arg Leu Trp Ser Ser
260 265
<210> 37
<211> 497
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Met Gly Ser Leu Glu Met Val Pro Met Gly Ala Gly Pro Pro Ser Pro
1 5 10 15
Gly Gly Asp Pro Asp Gly Tyr Asp Gly Gly Asn Asn Ser Gln Tyr Pro
20 25 30
Ser Ala Ser Gly Ser Ser Gly Asn Thr Pro Thr Pro Pro Asn Asp Glu
35 40 45
Glu Arg Glu Ser Asn Glu Glu Pro Pro Pro Pro Tyr Glu Asp Pro Tyr
50 55 60
Trp Gly Asn Gly Asp Arg His Ser Asp Tyr Gln Pro Leu Gly Thr Gln
65 70 75 80
Asp Gln Ser Leu Tyr Leu Gly Leu Gln His Asp Gly Asn Asp Gly Leu
85 90 95
Pro Pro Pro Pro Tyr Ser Pro Arg Asp Asp Ser Ser Gln His Ile Tyr
100 105 110
Glu Glu Ala Gly Arg Gly Ser Met Asn Pro Val Cys Leu Pro Val Ile
115 120 125
Val Ala Pro Tyr Leu Phe Trp Leu Ala Ala Ile Ala Ala Ser Cys Phe
130 135 140
Thr Ala Ser Val Ser Thr Val Val Thr Ala Thr Gly Leu Ala Leu Ser
145 150 155 160
Leu Leu Leu Leu Ala Ala Val Ala Ser Ser Tyr Ala Ala Ala Gln Arg
165 170 175
Lys Leu Leu Thr Pro Val Thr Val Leu Thr Ala Val Val Thr Phe Phe
180 185 190
Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn Ser Leu
195 200 205
Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile Tyr Val
210 215 220
Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg Trp Arg
225 230 235 240
Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys Val Leu Val
245 250 255
Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu Gly Ala Val
260 265 270
Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Val Leu Trp Leu
275 280 285
Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu Thr Leu
290 295 300
Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr Leu Asn
305 310 315 320
Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val Val Leu
325 330 335
Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Ser Lys Ile Leu Leu
340 345 350
Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala Ser Ala
355 360 365
Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser Leu Ser
370 375 380
Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu Ile Val
385 390 395 400
Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr Glu Trp Gly Ser Gly
405 410 415
Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu Gly Gly Leu Leu Thr
420 425 430
Met Val Ala Gly Ala Val Trp Leu Thr Val Met Ser Asn Thr Leu Leu
435 440 445
Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile Phe Leu Ile Gly Phe
450 455 460
Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr Cys Cys Tyr Tyr Cys
465 470 475 480
Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr Pro Tyr Arg Asn Thr
485 490 495
Val
<210> 38
<211> 497
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Met Gly Ser Leu Glu Met Val Pro Met Gly Ala Gly Pro Pro Ser Pro
1 5 10 15
Gly Gly Asp Pro Asp Gly Tyr Asp Gly Gly Asn Asn Ser Gln Tyr Pro
20 25 30
Ser Ala Ser Gly Ser Ser Gly Asn Thr Pro Thr Pro Pro Asn Asp Glu
35 40 45
Glu Arg Glu Ser Asn Glu Glu Pro Pro Pro Pro Tyr Glu Asp Pro Tyr
50 55 60
Trp Gly Asn Gly Asp Arg His Ser Asp Tyr Gln Pro Leu Gly Thr Gln
65 70 75 80
Asp Gln Ser Leu Tyr Leu Gly Leu Gln His Asp Gly Asn Asp Gly Leu
85 90 95
Pro Pro Pro Pro Tyr Ser Pro Arg Asp Asp Ser Ser Gln His Ile Tyr
100 105 110
Glu Glu Ala Gly Arg Gly Ser Met Asn Pro Val Cys Leu Pro Val Ile
115 120 125
Val Ala Pro Tyr Leu Phe Trp Leu Ala Ala Ile Ala Ala Ser Cys Phe
130 135 140
Thr Ala Ser Val Ser Thr Val Val Thr Ala Thr Gly Leu Ala Leu Ser
145 150 155 160
Leu Leu Leu Leu Ala Ala Val Ala Ser Ser Tyr Ala Ala Ala Gln Arg
165 170 175
Lys Leu Leu Thr Pro Val Thr Val Leu Thr Ala Val Val Thr Phe Phe
180 185 190
Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn Ser Leu
195 200 205
Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile Tyr Val
210 215 220
Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg Trp Arg
225 230 235 240
Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys Val Leu Val
245 250 255
Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu Gly Ala Val
260 265 270
Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Val Leu Trp Leu
275 280 285
Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu Thr Leu
290 295 300
Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr Leu Asn
305 310 315 320
Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val Val Leu
325 330 335
Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Thr Lys Ile Leu Leu
340 345 350
Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala Ser Ala
355 360 365
Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser Leu Ser
370 375 380
Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu Ile Val
385 390 395 400
Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr Glu Trp Gly Ser Gly
405 410 415
Asn Arg Thr Tyr Gly Pro Val Phe Met Ser Leu Gly Gly Leu Leu Thr
420 425 430
Met Val Ala Gly Ala Val Trp Leu Thr Val Met Ser Asn Thr Leu Leu
435 440 445
Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile Phe Leu Ile Gly Phe
450 455 460
Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr Cys Cys Tyr Tyr Cys
465 470 475 480
Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr Pro Tyr Arg Asn Thr
485 490 495
Val
<210> 39
<211> 1812
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 39
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc aggggcgatg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttccggcgg aaacggagcg gaagcggagc tactaacttc 960
agcctgctga agcaggctgg agacgtggag gagaaccctg gacctatgaa gaggatattg 1020
ggagctctgc tggggctctt gagtgcccag gtttgctgtg tgagaggaat acaagtggag 1080
cagagtcctc cagacctgat tctccaggag ggagccaatt ccacgctgcg gtgcaatttt 1140
tctgactctg tgaacaattt gcagtggttt catcaaaacc cttggggaca gctcatcaac 1200
ctgttttaca ttccctcagg gacaaaacag aatggaagat taagcgccac gactgtcgct 1260
acggaacgct acagcttatt gtacatttcc tcttcccaga ccacagactc aggcgtttat 1320
ttctgtgctg ttctaaataa caatgacatg cgctttggag cagggaccag actgacagta 1380
aaaccaaata tccagaaccc tgaccctgcc gtgtaccagc tgagagactc taaatccagt 1440
gacaagtctg tctgcctatt caccgatttt gattctcaaa caaatgtgtc acaaagtaag 1500
gattctgatg tgtatatcac agacaaaact gtgctagaca tgaggtctat ggacttcaag 1560
agcaacagtg ctgtggcctg gagcaacaaa tctgactttg catgtgcaaa cgccttcaac 1620
aacagcatta ttccagaaga caccttcttc cccagcccag aaagttcctg tgatgtcaag 1680
ctggtcgaga aaagctttga aacagatacg aacctaaact ttcaaaacct gtcagtgatt 1740
gggttccgaa tcctcctcct gaaagtggcc gggtttaatc tgctcatgac gctgcggctg 1800
tggtccagct ga 1812
<210> 40
<211> 1812
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 40
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc ccgggaggtg gtatgagcag 360
ttcttcgggc cagggacacg gctcaccgtg ctagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttccggcgg aaacggagcg gaagcggagc tactaacttc 960
agcctgctga agcaggctgg agacgtggag gagaaccctg gacctatgaa gaggatattg 1020
ggagctctgc tggggctctt gagtgcccag gtttgctgtg tgagaggaat acaagtggag 1080
cagagtcctc cagacctgat tctccaggag ggagccaatt ccacgctgcg gtgcaatttt 1140
tctgactctg tgaacaattt gcagtggttt catcaaaacc cttggggaca gctcatcaac 1200
ctgttttaca ttccctcagg gacaaaacag aatggaagat taagcgccac gactgtcgct 1260
acggaacgct acagcttatt gtacatttcc tcttcccaga ccacagactc aggcgtttat 1320
ttctgtgctg tggtcgataa caatgacatg cgctttggag cagggaccag actgacagta 1380
aaaccaaata tccagaaccc tgaccctgcc gtgtaccagc tgagagactc taaatccagt 1440
gacaagtctg tctgcctatt caccgatttt gattctcaaa caaatgtgtc acaaagtaag 1500
gattctgatg tgtatatcac agacaaaact gtgctagaca tgaggtctat ggacttcaag 1560
agcaacagtg ctgtggcctg gagcaacaaa tctgactttg catgtgcaaa cgccttcaac 1620
aacagcatta ttccagaaga caccttcttc cccagcccag aaagttcctg tgatgtcaag 1680
ctggtcgaga aaagctttga aacagatacg aacctaaact ttcaaaacct gtcagtgatt 1740
gggttccgaa tcctcctcct gaaagtggcc gggtttaatc tgctcatgac gctgcggctg 1800
tggtccagct ga 1812
<210> 41
<211> 1812
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 41
atgggcttca ggctcctctg ctgtgtggcc ttttgtctcc tgggagcagg cccagtggat 60
tctggagtca cacaaacccc aaagcacctg atcacagcaa ctggacagcg agtgacgctg 120
agatgctccc ctaggtctgg agacctctct gtgtactggt accaacagag cctggaccag 180
ggcctccagt tcctcattca gtattataat ggagaagaga gagcaaaagg aaacattctt 240
gaacgattct ccgcacaaca gttccctgac ttgcactctg aactaaacct gagctctctg 300
gagctggggg actcagcttt gtatttctgt gccagcagcg taggtccatg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttccggcgg aaacggagcg gaagcggagc tactaacttc 960
agcctgctga agcaggctgg agacgtggag gagaaccctg gacctatgaa gaggatattg 1020
ggagctctgc tggggctctt gagtgcccag gtttgctgtg tgagaggaat acaagtggag 1080
cagagtcctc cagacctgat tctccaggag ggagccaatt ccacgctgcg gtgcaatttt 1140
tctgactctg tgaacaattt gcagtggttt catcaaaacc cttggggaca gctcatcaac 1200
ctgttttaca ttccctcagg gacaaaacag aatggaagat taagcgccac gactgtcgct 1260
acggaacgct acagcttatt gtacatttcc tcttcccaga ccacagactc aggcgtttat 1320
ttctgtgctg tgctaaataa caatgacatg cgctttggag cagggaccag actgacagta 1380
aaaccaaata tccagaaccc tgaccctgcc gtgtaccagc tgagagactc taaatccagt 1440
gacaagtctg tctgcctatt caccgatttt gattctcaaa caaatgtgtc acaaagtaag 1500
gattctgatg tgtatatcac agacaaaact gtgctagaca tgaggtctat ggacttcaag 1560
agcaacagtg ctgtggcctg gagcaacaaa tctgactttg catgtgcaaa cgccttcaac 1620
aacagcatta ttccagaaga caccttcttc cccagcccag aaagttcctg tgatgtcaag 1680
ctggtcgaga aaagctttga aacagatacg aacctaaact ttcaaaacct gtcagtgatt 1740
gggttccgaa tcctcctcct gaaagtggcc gggtttaatc tgctcatgac gctgcggctg 1800
tggtccagct ga 1812
<210> 42
<211> 1812
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 42
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc cggggcggtg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttccggcgg aaacggagcg gaagcggagc tactaacttc 960
agcctgctga agcaggctgg agacgtggag gagaaccctg gacctatgaa gaggatattg 1020
ggagctctgc tggggctctt gagtgcccag gtttgctgtg tgagaggaat acaagtggag 1080
cagagtcctc cagacctgat tctccaggag ggagccaatt ccacgctgcg gtgcaatttt 1140
tctgactctg tgaacaattt gcagtggttt catcaaaacc cttggggaca gctcatcaac 1200
ctgttttaca ttccctcagg gacaaaacag aatggaagat taagcgccac gactgtcgct 1260
acggaacgct acagcttatt gtacatttcc tcttcccaga ccacagactc aggcgtttat 1320
ttctgtgctg tggtcgataa caatgacatg cgctttggag cagggaccag actgacagta 1380
aaaccaaata tccagaaccc tgaccctgcc gtgtaccagc tgagagactc taaatccagt 1440
gacaagtctg tctgcctatt caccgatttt gattctcaaa caaatgtgtc acaaagtaag 1500
gattctgatg tgtatatcac agacaaaact gtgctagaca tgaggtctat ggacttcaag 1560
agcaacagtg ctgtggcctg gagcaacaaa tctgactttg catgtgcaaa cgccttcaac 1620
aacagcatta ttccagaaga caccttcttc cccagcccag aaagttcctg tgatgtcaag 1680
ctggtcgaga aaagctttga aacagatacg aacctaaact ttcaaaacct gtcagtgatt 1740
gggttccgaa tcctcctcct gaaagtggcc gggtttaatc tgctcatgac gctgcggctg 1800
tggtccagct ga 1812
<210> 43
<211> 1812
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 43
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc aagggcggtg gtacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttccggcgg aaacggagcg gaagcggagc tactaacttc 960
agcctgctga agcaggctgg agacgtggag gagaaccctg gacctatgaa gaggatattg 1020
ggagctctgc tggggctctt gagtgcccag gtttgctgtg tgagaggaat acaagtggag 1080
cagagtcctc cagacctgat tctccaggag ggagccaatt ccacgctgcg gtgcaatttt 1140
tctgactctg tgaacaattt gcagtggttt catcaaaacc cttggggaca gctcatcaac 1200
ctgttttaca ttccctcagg gacaaaacag aatggaagat taagcgccac gactgtcgct 1260
acggaacgct acagcttatt gtacatttcc tcttcccaga ccacagactc aggcgtttat 1320
ttctgtgctg tgctagataa caatgacatg cgctttggag cagggaccag actgacagta 1380
aaaccaaata tccagaaccc tgaccctgcc gtgtaccagc tgagagactc taaatccagt 1440
gacaagtctg tctgcctatt caccgatttt gattctcaaa caaatgtgtc acaaagtaag 1500
gattctgatg tgtatatcac agacaaaact gtgctagaca tgaggtctat ggacttcaag 1560
agcaacagtg ctgtggcctg gagcaacaaa tctgactttg catgtgcaaa cgccttcaac 1620
aacagcatta ttccagaaga caccttcttc cccagcccag aaagttcctg tgatgtcaag 1680
ctggtcgaga aaagctttga aacagatacg aacctaaact ttcaaaacct gtcagtgatt 1740
gggttccgaa tcctcctcct gaaagtggcc gggtttaatc tgctcatgac gctgcggctg 1800
tggtccagct ga 1812
<210> 44
<211> 1812
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 44
atgggctgca ggctgctctg ctgtgcggtt ctctgtctcc tgggagcagt tcccatagac 60
actgaagtta cccagacacc aaaacacctg gtcatgggaa tgacaaataa gaagtctttg 120
aaatgtgaac aacatatggg gcacagggct atgtattggt acaagcagaa agctaagaag 180
ccaccggagc tcatgtttgt ctacagctat gagaaactct ctataaatga aagtgtgcca 240
agtcgcttct cacctgaatg ccccaacagc tctctcttaa accttcacct acacgccctg 300
cagccagaag actcagccct gtatctctgc gccagcagcc ccgggcgatt ctacgagcag 360
tacttcgggc cgggcaccag gctcacggtc acagaggacc tgaaaaacgt gttcccaccc 420
gaggtcgctg tgtttgagcc atcagaagca gagatctccc acacccaaaa ggccacactg 480
gtgtgcctgg ccacaggctt cttccccgac cacgtggagc tgagctggtg ggtgaatggg 540
aaggaggtgc acagtggggt cagcacagac ccgcagcccc tcaaggagca gcccgccctc 600
aatgactcca gatactgcct gagcagccgc ctgagggtct cggccacctt ctggcagaac 660
ccccgcaacc acttccgctg tcaagtccag ttctacgggc tctcggagaa tgacgagtgg 720
acccaggata gggccaaacc cgtcacccag atcgtcagcg ccgaggcctg gggtagagca 780
gactgtggct ttacctcggt gtcctaccag caaggggtcc tgtctgccac catcctctat 840
gagatcctgc tagggaaggc caccctgtat gctgtgctgg tcagcgccct tgtgttgatg 900
gccatggtca agagaaagga tttccggcgg aaacggagcg gaagcggagc tactaacttc 960
agcctgctga agcaggctgg agacgtggag gagaaccctg gacctatgaa gaggatattg 1020
ggagctctgc tggggctctt gagtgcccag gtttgctgtg tgagaggaat acaagtggag 1080
cagagtcctc cagacctgat tctccaggag ggagccaatt ccacgctgcg gtgcaatttt 1140
tctgactctg tgaacaattt gcagtggttt catcaaaacc cttggggaca gctcatcaac 1200
ctgttttaca ttccctcagg gacaaaacag aatggaagat taagcgccac gactgtcgct 1260
acggaacgct acagcttatt gtacatttcc tcttcccaga ccacagactc aggcgtttat 1320
ttctgtgctg tccttaataa caatgacatg cgctttggag cagggaccag actgacagta 1380
aaaccaaata tccagaaccc tgaccctgcc gtgtaccagc tgagagactc taaatccagt 1440
gacaagtctg tctgcctatt caccgatttt gattctcaaa caaatgtgtc acaaagtaag 1500
gattctgatg tgtatatcac agacaaaact gtgctagaca tgaggtctat ggacttcaag 1560
agcaacagtg ctgtggcctg gagcaacaaa tctgactttg catgtgcaaa cgccttcaac 1620
aacagcatta ttccagaaga caccttcttc cccagcccag aaagttcctg tgatgtcaag 1680
ctggtcgaga aaagctttga aacagatacg aacctaaact ttcaaaacct gtcagtgatt 1740
gggttccgaa tcctcctcct gaaagtggcc gggtttaatc tgctcatgac gctgcggctg 1800
tggtccagct ga 1812
<210> 45
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 45
atgagcatcg gcctcctgtg 20
<210> 46
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 46
atggatacct ggctcgtatg c 21
<210> 47
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 47
atgggctgca ggctcctc 18
<210> 48
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 48
atgggctgca ggctgctc 18
<210> 49
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 49
atgggctcca ggctgctct 19
<210> 50
<211> 14
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 50
atgggccccg ggct 14
<210> 51
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 51
atgggccctg ggctcct 17
<210> 52
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 52
atgggaccca ggctcctct 19
<210> 53
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 53
atgagcatcg ggctcctgtg 20
<210> 54
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 54
atgagcctcg ggctcctg 18
<210> 55
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 55
atgagaatca ggctcctgtg c 21
<210> 56
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 56
atgagcatca gcctcctgtg 20
<210> 57
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 57
atgggcacaa ggctcctctg 20
<210> 58
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 58
atgggcacca ggctcctc 18
<210> 59
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 59
atgggcacca gtctcctatg c 21
<210> 60
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 60
atgggtacca gtctcctatg ctg 23
<210> 61
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 61
atgggcacca gcctcctc 18
<210> 62
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 62
atgggcttca ggctcctctg 20
<210> 63
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 63
atgggcacga ggctcttctt c 21
<210> 64
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 64
atgggcacca ggctcttctt c 21
<210> 65
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 65
atgggcacaa ggttgttctt c 21
<210> 66
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 66
atgagcacca ggcttctctg c 21
<210> 67
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 67
atgggtacca ggctcctctg 20
<210> 68
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 68
atggactcct ggaccttctg ct 22
<210> 69
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 69
atggactcct ggaccctctg 20
<210> 70
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 70
atggccacca ggctcctc 18
<210> 71
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 71
atgcttagtc ctgacctgcc tg 22
<210> 72
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 72
atggtttcca ggcttctcag tt 22
<210> 73
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 73
atgggtcctg ggcttctcc 19
<210> 74
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 74
atgagcccaa tattcacctg ca 22
<210> 75
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 75
atggatatct ggctcctctg ct 22
<210> 76
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 76
atggacacca gagtactctg ctg 23
<210> 77
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 77
atgagcaacc aggtgctctg 20
<210> 78
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 78
atgctgctgc ttctgctgc 19
<210> 79
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 79
atggcctccc tgctcttctt c 21
<210> 80
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 80
atgactatca ggctcctctg ctac 24
<210> 81
<211> 16
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 81
atgggccccc agctcc 16
<210> 82
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 82
atgggaatca ggctcctctg tc 22
<210> 83
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 83
atgctgagtc ttctgctcct tctc 24
<210> 84
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 84
atgctctgct ctctccttgc 20
<210> 85
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 85
acagaggatt tcccgctcag 20
<210> 86
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 86
tcactctgaa gatccggtcc ac 22
<210> 87
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 87
cttcacatca attccctgga gc 22
<210> 88
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 88
cacctgaatg ccccaacag 19
<210> 89
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 89
agtcgcttct cacctgaatg c 21
<210> 90
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 90
gagatgaatg tgagcacctt ggag 24
<210> 91
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 91
gagatgaatg tgagtgcctt ggag 24
<210> 92
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 92
gctctgagct gaatgtgaac gc 22
<210> 93
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 93
gaagtcccca atggctacaa tg 22
<210> 94
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 94
aggtccctga tggctacaat g 21
<210> 95
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 95
tggcgtctgc tgtaccctct 20
<210> 96
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 96
cccctcaagc tggagtcagc 20
<210> 97
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 97
acacagagga tttcccactc agg 23
<210> 98
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 98
ttctctgcac agaggtctga gg 22
<210> 99
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 99
gctgcccagt gatcgcttct 20
<210> 100
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 100
actctgaaga tccagcgcac ag 22
<210> 101
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 101
cgtctccact ctgaagatcc agc 23
<210> 102
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 102
ggcctgaggg atccatctcc 20
<210> 103
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 103
ggctgctcag tgatcggttc 20
<210> 104
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 104
gaacgattct ccgcacaaca gt 22
<210> 105
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 105
acaaaggaga agtctcagat ggct 24
<210> 106
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 106
ccctcactct ggagtcagct ac 22
<210> 107
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 107
cctcactctg gagtccgcta c 21
<210> 108
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 108
gcagagaggc tcaaaggagt agac 24
<210> 109
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 109
atccagccct cagaacccag 20
<210> 110
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 110
atcattctga actgaacatg agctc 25
<210> 111
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 111
tggagggacg tattctactc tgaag 25
<210> 112
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 112
gacacccctg ataacttcca atcc 24
<210> 113
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 113
tgcctcccaa attcaccctg 20
<210> 114
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 114
catcccgcag agccgag 17
<210> 115
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 115
gcaggtagtg cgaggagatt c 21
<210> 116
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 116
ctgtgacatc ggcccaaaag 20
<210> 117
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 117
acagtgacca gtgcccatcc 20
<210> 118
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 118
caatgcccca agaacgcac 19
<210> 119
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 119
tagagtctgc catccccaac c 21
<210> 120
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 120
gacggagcat tttcccctga c 21
<210> 121
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 121
gccagcacca accagacatc 20
<210> 122
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 122
ctgatcctgg agtcgcccag 20
<210> 123
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 123
atcagccgcc caaacctaac 20
<210> 124
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 124
cggcagttca tcctgagttc taag 24
<210> 125
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 125
atggaaactc tcctgggagt gtc 23
<210> 126
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 126
atgtggggag ctttccttct ct 22
<210> 127
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 127
atgtggggag ttttccttct ttatg 25
<210> 128
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 128
atggctttgc agagcactct g 21
<210> 129
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 129
atggcctctg cacccatctc 20
<210> 130
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 130
atgaggcaag tggcgagagt 20
<210> 131
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 131
atgaagacat ttgctggatt ttcg 24
<210> 132
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 132
atggagtcat tcctgggagg tg 22
<210> 133
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 133
atggagaaga tgcggagacc tg 22
<210> 134
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 134
atgctcctgt tgctcatacc ag 22
<210> 135
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 135
atgctcctgc tgctcgtcc 19
<210> 136
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 136
atgctcctgg agcttatccc a 21
<210> 137
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 137
atgctcttag tggtcattct gctg 24
<210> 138
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 138
atgaattctt ctccaggacc agc 23
<210> 139
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 139
atgaactatt ctccaggctt agtatctc 28
<210> 140
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 140
atgaaaaagc atctgacgac cttc 24
<210> 141
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 141
atgatatcct tgagagtttt actggtg 27
<210> 142
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 142
atgaaatcct tgagagtttt actagtgatc 30
<210> 143
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 143
atgatgaaat ccttgagagt tttactgg 28
<210> 144
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 144
atgacatcca ttcgagctgt atttat 26
<210> 145
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 145
atggcaggca ttcgagctt 19
<210> 146
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 146
atgtcacttt ctagcctgct gaag 24
<210> 147
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 147
atgaagccca ccctcatctc ag 22
<210> 148
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 148
atgctgtctg cttcctgctc ag 22
<210> 149
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 149
atgctgactg ccagcctgt 19
<210> 150
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 150
atggagaaaa tgttggagtg tgc 23
<210> 151
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 151
atggagaccc tcttgggcct 20
<210> 152
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 152
atgaagagga tattgggagc tctg 24
<210> 153
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 153
atggacaaga tcttaggagc atcat 25
<210> 154
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 154
atgctgttct ccagcctgct 20
<210> 155
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 155
atggagaaga atcctttggc ag 22
<210> 156
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 156
atgctactca tcacatcaat gttgg 25
<210> 157
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 157
atgaggctgg tggcaagagt aac 23
<210> 158
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 158
atgaagttgg tgacaagcat tactg 25
<210> 159
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 159
atggtcctga aattctccgt gtc 23
<210> 160
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 160
atggccatgc tcctggg 17
<210> 161
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 161
atggagactc tcctgaaagt gct 23
<210> 162
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 162
atggagactg ttctgcaagt actcc 25
<210> 163
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 163
atgctccttg aacatttatt aataatct 28
<210> 164
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 164
atgatgaagt gtccacaggc tttac 25
<210> 165
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 165
atgacacgag ttagcttgct gtg 23
<210> 166
<211> 18
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 166
atggcatgcc ctggcttc 18
<210> 167
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 167
atgaagaagc tactagcaat gattctg 27
<210> 168
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 168
atgaactcct ctctggactt tctaattc 28
<210> 169
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 169
atggtgaaga tccggcaatt 20
<210> 170
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 170
agattaagag tcacgcttga cacttc 26
<210> 171
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 171
tccttagtcg ctctgatagt tatggt 26
<210> 172
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 172
tttcttcatt ccttagtcgg tctaaag 27
<210> 173
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 173
ctcttcatcg ctgctcatcc tc 22
<210> 174
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 174
gccaaacctc cttccacctg 20
<210> 175
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 175
cctgccgaca gaaagtccag 20
<210> 176
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 176
cgcattgcag acacccagac 20
<210> 177
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 177
ttgataccac ccttaaacag agtttg 26
<210> 178
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 178
attactgaag aatggaagca gcttg 25
<210> 179
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 179
tcctttaatc tgaggaaacc ctctg 25
<210> 180
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 180
gtgaaacctc cttccacctg ac 22
<210> 181
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 181
aggctttgag gctgaattta agag 24
<210> 182
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 182
ggctgaattt aacaagagtc aaacttc 27
<210> 183
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 183
gagcgaaacc tccttctacc tg 22
<210> 184
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 184
aaaccacttc tttccacttg gag 23
<210> 185
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 185
caaagcaaag ctctctgcac atc 23
<210> 186
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 186
cagtgattca gccacctacc tc 22
<210> 187
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 187
cgaattgctg ttacattgaa caagac 26
<210> 188
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 188
ttgcagctac tcaacctgga gac 23
<210> 189
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 189
atccgccaac cttgtcatct c 21
<210> 190
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 190
aaggcgagac atctttccac c 21
<210> 191
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 191
gccagtccta tcaagagtga cagttc 26
<210> 192
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 192
caacttcacc atcacagcct cac 23
<210> 193
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 193
cacatcacag cccctaaacc tg 22
<210> 194
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 194
tggaagactt aatgcctcgc tg 22
<210> 195
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 195
tgtcgctacg gaacgctaca g 21
<210> 196
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 196
cttcaataaa agtgccaagc agttc 25
<210> 197
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 197
aaaaagtggt cgctattctg tcaac 25
<210> 198
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 198
gaagaaagga cgaataagtg ccac 24
<210> 199
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 199
acatcacagc cacccagact ac 22
<210> 200
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 200
cacagaagac agaaagtcca gcac 24
<210> 201
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 201
gcaatcgctg aagacagaaa gtc 23
<210> 202
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 202
gaaaggacag ttctctccac atcac 25
<210> 203
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 203
aaaagtgcca agcacctctc tc 22
<210> 204
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 204
gcaaagctcc ctgtacctta cg 22
<210> 205
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 205
aaagataact gccaagttgg atgag 25
<210> 206
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 206
cttcctgaat atctcagcat ccatac 26
<210> 207
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 207
gcatcctgaa catcacagcc ac 22
<210> 208
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 208
gaatcgtttc tctgtgaact tccag 25
<210> 209
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 209
tctcagcacc ctccacatca c 21
<210> 210
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 210
caggtatcag actcagccgt gtac 24
<210> 211
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 211
gccacaataa acatacagga aaagc 25
<210> 212
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 212
Asp Ser Val Asn Asn
1 5
<210> 213
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 213
Ile Pro Ser Gly Thr
1 5
<210> 214
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 214
Ala Val Leu Asn Asn Asn Asp Met Arg
1 5
<210> 215
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 215
Ala Val Val Asp Asn Asn Asp Met Arg
1 5
<210> 216
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 216
Ala Val Leu Asp Asn Asn Asp Met Arg
1 5
<210> 217
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 217
Met Gly His Arg Ala
1 5
<210> 218
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 218
Ser Gly Asp Leu Ser
1 5
<210> 219
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 219
Tyr Ser Tyr Glu Lys Leu
1 5
<210> 220
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 220
Tyr Tyr Asn Gly Glu Glu
1 5
<210> 221
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 221
Ala Ser Ser Gln Gly Arg Trp Tyr Glu Gln Tyr
1 5 10
<210> 222
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 222
Ala Ser Ser Val Gly Pro Trp Tyr Glu Gln Tyr
1 5 10
<210> 223
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 223
Ala Ser Ser Pro Gly Arg Trp Tyr Glu Gln Phe
1 5 10
<210> 224
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 224
Ala Ser Ser Pro Gly Arg Phe Tyr Glu Gln Tyr
1 5 10
<210> 225
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 225
Arg Arg Lys Arg Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys
1 5 10 15
Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro
20 25
<210> 226
<211> 81
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 226
cggcggaaac ggagcggaag cggagctact aacttcagcc tgctgaagca ggctggagac 60
gtggaggaga accctggacc t 81
<210> 227
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 227
tcaggcagta tctggagtca ttg 23
<210> 228
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 228
gcacctcctt cccattcacc 20
<210> 229
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 229
gcttctgatg gctcaaacac ag 22
<210> 230
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 230
cgaccagctt gacatcacag 20
<210> 231
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 231
gttgctcttg aagtccatag acctc 25
<210> 232
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 232
cagggtcagg gttctggata 20
<210> 233
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 233
atttcaggtg tcgtgaagcg gccgcgccac catgggctgc aggctgctc 49
<210> 234
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 234
atttcaggtg tcgtgaagcg gccgcgccac catgggctgc aggctgctc 49
<210> 235
<211> 51
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 235
atttcaggtg tcgtgaagcg gccgcgccac catgggcttc aggctcctct g 51
<210> 236
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 236
atttcaggtg tcgtgaagcg gccgcgccac catgggctgc aggctgctc 49
<210> 237
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 237
atttcaggtg tcgtgaagcg gccgcgccac catgggctgc aggctgctc 49
<210> 238
<211> 49
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 238
atttcaggtg tcgtgaagcg gccgcgccac catgggctgc aggctgctc 49
<210> 239
<211> 81
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 239
tctccagcct gcttcagcag gctgaagtta gtagctccgc ttccgctccg tttccgccgg 60
aaatcctttc tcttgaccat g 81
<210> 240
<211> 71
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 240
tcagcctgct gaagcaggct ggagacgtgg aggagaaccc tggacctatg aagaggatat 60
tgggagctct g 71
<210> 241
<211> 71
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 241
tcagcctgct gaagcaggct ggagacgtgg aggagaaccc tggacctatg aagaggatat 60
tgggagctct g 71
<210> 242
<211> 71
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 242
tcagcctgct gaagcaggct ggagacgtgg aggagaaccc tggacctatg aagaggatat 60
tgggagctct g 71
<210> 243
<211> 71
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 243
tcagcctgct gaagcaggct ggagacgtgg aggagaaccc tggacctatg aagaggatat 60
tgggagctct g 71
<210> 244
<211> 71
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 244
tcagcctgct gaagcaggct ggagacgtgg aggagaaccc tggacctatg aagaggatat 60
tgggagctct g 71
<210> 245
<211> 71
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 245
tcagcctgct gaagcaggct ggagacgtgg aggagaaccc tggacctatg aagaggatat 60
tgggagctct g 71
<210> 246
<211> 45
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 246
agggatcctc tagactcgag ctagctcagc tggaccacag ccgca 45
<210> 247
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 247
caccgtctct cagctggtac acggc 25
<210> 248
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 248
aaacgccgtg taccagctga gagac 25
<210> 249
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 249
caccgggctc aaacacagcg acctc 25
<210> 250
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 250
aaacgaggtc gctgtgtttg agccc 25
<210> 251
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 251
Ala Ser Ser Pro Gly Arg Trp Tyr Glu Gln Tyr
1 5 10
Claims (12)
1.一种T细胞抗原受体,其特征在于,所述的T细胞抗原受体特异性结合EBV潜伏期膜蛋白LMP2,其中,所述LMP2的结合表位包含SEQ ID NO:5和/或6;
优选的,所述的T细胞抗原受体包含α链的CDR1α-CDR3α和β链的CDR1β-CDR3β,其中,CDR1α的氨基酸序列如SEQ ID NO:212所示或与SEQ ID NO:212所示氨基酸序列具有至少80%同源性,CDR2α的氨基酸序列如SEQ ID NO:213所示或与SEQ ID NO:213所示氨基酸序列具有至少80%同源性,CDR3α的氨基酸序列如SEQ ID NO:214-215中的任一种或与SEQ IDNO:214-215中任一种所示氨基酸序列具有至少80%同源性,CDR1β的氨基酸序列如SEQ IDNO:217或与SEQ ID NO:217所示氨基酸序列具有至少80%同源性,CDR2β的氨基酸序列如SEQ ID NO:219或与SEQ ID NO:219所示氨基酸序列具有至少80%同源性,CDR3β的氨基酸序列如SEQ ID NO:221、251中的任一种或与SEQ ID NO:221、251中任一种所示氨基酸序列具有至少80%同源性;
进一步优选的,所述的CDR1α-CDR3α及CDR1β-CDR3β选自下列任一组:
2.根据权利要求1所述的T细胞抗原受体,其特征在于,所述的α链的氨基酸序列如SEQID NO:31-36所示,或与SEQ ID NO:31-36所示氨基酸序列具有至少80%同源性;所述的β链的氨基酸序列如SEQ ID NO:25-30所示,或与SEQ ID NO:25-30所示氨基酸序列具有至少80%同源性;优选的,所述的T细胞抗原受体的氨基酸序列选自SEQ ID NO:19-24中的任一种或与SEQ ID NO:19-24任一种所示氨基酸序列具有至少80%同源性。
3.一种核酸,其特征在于,所述的核酸编码权利要求1-2任一所述的T细胞抗原受体。
4.一种表达载体,其特征在于,所述的表达载体包含权利要求3所述的核酸。
5.一种宿主细胞或免疫细胞,其特征在于,所述的宿主细胞包含权利要求3所述的核酸或权利要求4所述的表达载体,所述的免疫细胞表达权利要求1-2任一所述的T细胞抗原受体。
6.一种重组T细胞的制备方法,其特征在于,包括如下步骤:
1)从阳性T细胞克隆得到权利要求3的核酸序列;
2)分离、培养原代T细胞;
3)将步骤1)得到的核酸序列递送至步骤2)所述的原代T细胞中,获得表达权利要求1-2任一所述T细胞抗原受体的重组T细胞。
7.一种T细胞抗原受体的制备方法,其特征在于,包括如下步骤:
(1)从阳性T细胞克隆得到权利要求3的核酸序列;
(2)将步骤(1)得到的核酸序列连接至载体骨架,获得表达载体;
(3)将步骤(2)获得的表达载体转化至宿主细胞,然后诱导其表达;
(4)获得T细胞抗原受体。
8.一种多聚体复合物,其特征在于,所述多聚体复合物包含权利要求1-2任一所述的T细胞抗原受体。
9.根据权利要求8所述的多聚体复合物,其特征在于,所述多聚体复合物还包括单体,生物素分子,以及链霉亲和素分子或亲和素分子,其中,所述单体包括MHC分子α链胞外区和β2m链及抗原肽,所述单体与所述生物素分子偶联,所述生物素分子与所述链霉亲和素或亲和素分子结合;优选的,所述的抗原肽包含SEQ ID NO:5和/或6,所述的MHC分子为HLA-A*1101。
10.一种权利要求8-9任一所述的多聚体复合物的制备方法,其特征在于,包括如下步骤:
I)表达和纯化在C端连接avi-tag序列的MHC分子α链胞外区和β2m链;
II)将抗原肽、步骤I)获得的在C端连接avi-tag序列的MHC分子α链胞外区和β2m链复性折叠,制备单体;
III)将步骤II)制备的单体生物素化,获得生物素化的单体;
IV)将步骤III)获得的生物素化的单体与带荧光标记的链霉亲和素或亲和素反应,制备抗原肽-MHC分子四聚体;
V)将步骤IV)得到的抗原肽-MHC分子四聚体与T细胞共孵育,形成T细胞抗原受体与抗原肽-MHC分子四聚体复合物,钓取特异性T细胞抗原受体。
11.权利要求1-2任一所述的T细胞抗原受体、权利要求3所述的核酸、权利要求4所述的表达载体、权利要求5所述的宿主细胞、权利要求5所述的免疫细胞或者权利要求8-9任一所述的多聚体复合物的应用,其特征在于,所述的应用包括在制备诊断或治疗与EBV相关疾病的产品中的应用,或者在T细胞标记、检测、细胞分选或活化中的应用;
优选的,所述的与EBV相关疾病选自传染性单核细胞增多症、连锁淋巴细胞增生综合症、病毒性嗜血细胞综合症、口腔毛状黏膜白斑病、病毒性脑膜炎、周围神经炎、病毒性肺炎、病毒性心肌炎、鼻咽癌、霍奇金淋巴瘤、伯基特淋巴瘤、胃癌、肝细胞癌、淋巴上皮样肉瘤、唾液腺肿瘤、乳腺癌、胸腺瘤、原发性渗出性淋巴瘤或B/T/NK细胞淋巴瘤。
12.一种药物组合物或试剂盒,所述的药物组合物或试剂盒包含下列任一组:
i)权利要求1-2任一所述的T细胞抗原受体;
ii)权利要求3所述的核酸;
iii)权利要求4所述的表达载体;
iv)权利要求5所述的宿主细胞;
v)权利要求5所述的免疫细胞;或
vi)权利要求8-9任一所述的多聚体复合物。
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Cited By (2)
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CN113956349A (zh) * | 2014-11-26 | 2022-01-21 | 美国卫生和人力服务部 | 抗突变的kras的t细胞受体 |
WO2023092452A1 (zh) * | 2021-11-26 | 2023-06-01 | 上海吉倍生物技术有限公司 | 识别ebv lmp2抗原的t细胞受体及其应用 |
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WO2023242343A1 (en) * | 2022-06-15 | 2023-12-21 | Immunoscape Pte. Ltd. | Human t cell receptors specific for antigenic peptides derived from mitogen-activated protein kinase 8 interacting protein 2 (mapk8ip2), epstein-barr virus or human endogenous retrovirus, and uses thereof |
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EP1229043A1 (en) | 2001-01-30 | 2002-08-07 | Cyto-Barr B.V. | Peptides derived from Epstein Barr virus (EBV) proteins LMP1, LMP2 and BARF1 antibody reagents reactive therewith |
CN108289950B (zh) | 2015-06-09 | 2022-10-21 | 纪念斯隆凯特琳癌症中心 | 特异于人hla呈递的ebv潜伏膜蛋白2a肽的t细胞受体样抗体药剂 |
GB201520191D0 (en) | 2015-11-16 | 2015-12-30 | Cancer Rec Tech Ltd | T-cell receptor and uses thereof |
EA201992536A1 (ru) * | 2017-04-24 | 2020-03-05 | Оспедале Сан Раффаэле С.Р.Л. | Tcr и пептиды |
WO2020057619A1 (zh) * | 2018-09-21 | 2020-03-26 | 广东香雪精准医疗技术有限公司 | 一种识别afp抗原的高亲和力t细胞受体 |
CN109306005B (zh) | 2018-09-30 | 2019-11-15 | 清华大学 | 一种eb病毒特异性t细胞抗原受体及其应用 |
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Cited By (2)
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CN113956349A (zh) * | 2014-11-26 | 2022-01-21 | 美国卫生和人力服务部 | 抗突变的kras的t细胞受体 |
WO2023092452A1 (zh) * | 2021-11-26 | 2023-06-01 | 上海吉倍生物技术有限公司 | 识别ebv lmp2抗原的t细胞受体及其应用 |
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CN113621070A (zh) | 2021-11-09 |
CN113621048A (zh) | 2021-11-09 |
KR20230061292A (ko) | 2023-05-08 |
WO2021223604A1 (zh) | 2021-11-11 |
EP4148066A4 (en) | 2023-12-27 |
CN113621072A (zh) | 2021-11-09 |
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JP2023524602A (ja) | 2023-06-12 |
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